Stat3 &other target proteins in psoriasis by yousry a mawla

STAT 3 and Other TargetSTAT 3 and Other Target
Proteins :New Concepts inProteins :New Concepts in
PsoriasisPsoriasis
Pathogenesis&TherapyPathogenesis&Therapy
M.YOUSRY ABDEL-MAWLA,MDM.YOUSRY ABDEL-MAWLA,MD
Zagazig Faculty of Medicine,EgyptZagazig Faculty of Medicine,Egypt..

SignalSignal transducerstransducers andand activatorsactivators
ofof transcriptiontranscription)) Stat) FamilyStat) Family
StatsStats areare latentlatent inin thethe cytoplasmcytoplasm untiluntil theythey
areare activatedactivated byby extracellularextracellular signalingsignaling
ligandsligands,, includingincluding cytokinescytokines,, growthgrowth factorsfactors
andand hormones.hormones.
Binding of these extracellular ligands toBinding of these extracellular ligands to
the specific receptors leads to activation ofthe specific receptors leads to activation of
variousvarious Tyrosine kinases (TKs).Tyrosine kinases (TKs).
They include JAKs, receptor TKs, and non-They include JAKs, receptor TKs, and non-
receptor TKs such as Src and ABL, whichreceptor TKs such as Src and ABL, which
can directly phosphorylate Stat proteins incan directly phosphorylate Stat proteins in
the absence of ligand-induced receptorthe absence of ligand-induced receptor
signalingsignaling

Cytokines and growth factors that activate
STAT proteins

Structure of STAT3 protein.Structure of STAT3 protein.
Similar to other members of the STAT family,Similar to other members of the STAT family,
STAT3 is comprised of six domains: N-STAT3 is comprised of six domains: N-
terminal domain, coiled-coil domain, DNAterminal domain, coiled-coil domain, DNA
binding domain, linker domain, SH2 domainbinding domain, linker domain, SH2 domain
and Tran activation domain.and Tran activation domain.

STAT3 ActivationSTAT3 Activation
Stat3 is activated by cytokines of the IL-6Stat3 is activated by cytokines of the IL-6
family such as IL-6, IL-11, leukemia inhibitoryfamily such as IL-6, IL-11, leukemia inhibitory
factor (LIF), ciliary neurotrophic factorfactor (LIF), ciliary neurotrophic factor
(CNTF), oncostatin M and cardiotropin I .(CNTF), oncostatin M and cardiotropin I .
Stat3 is the major signal transducerStat3 is the major signal transducer
downstream of gp130-like receptorsdownstream of gp130-like receptors ..
Other extracellular signaling ligands suchOther extracellular signaling ligands such
as IL-10 family members, epidermal growthas IL-10 family members, epidermal growth
factor (EGF), platelet derived growth factorfactor (EGF), platelet derived growth factor
(PDGF), hepa- tocyte growth factor (HGF),(PDGF), hepa- tocyte growth factor (HGF),
granulocyte colony- stimulating factor (G-granulocyte colony- stimulating factor (G-
CSF) and leptin have also known toCSF) and leptin have also known to
activate Stat3.activate Stat3.

Mechanism of Stat3 signalingMechanism of Stat3 signaling
Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such asDifferent tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as
EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3
through activation of intermediary kineases of the SRC and JAK families. Cytokinesthrough activation of intermediary kineases of the SRC and JAK families. Cytokines
such as IL-6 family members bind to gp130, a common receptor subunit, thereby JAKsuch as IL-6 family members bind to gp130, a common receptor subunit, thereby JAK
families and subsequent Stat3 are activated. Non-receptor TKs such as SRCfamilies and subsequent Stat3 are activated. Non-receptor TKs such as SRC
and ABL can directly phophorylate Stat3 in the absence of ligand-dependentand ABL can directly phophorylate Stat3 in the absence of ligand-dependent
receptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins formreceptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins form
dimers, enter the nucleus and bind DNA to activate transcription of the target genesdimers, enter the nucleus and bind DNA to activate transcription of the target genes

Regulation of the STAT3 signalRegulation of the STAT3 signal
transduction pathwaytransduction pathway
Cytokine-binding induces receptor oligomerization thatCytokine-binding induces receptor oligomerization that
facilitates cross-phosphorylation and activation of receptor-facilitates cross-phosphorylation and activation of receptor-
associated JAK kinases.associated JAK kinases.
Recruitment of STAT3 proteins to the activated receptorRecruitment of STAT3 proteins to the activated receptor
complex results in their activation, dimerization andcomplex results in their activation, dimerization and
translocation into the nucleustranslocation into the nucleus
In the nucleus they to induce the expression of cytokine-In the nucleus they to induce the expression of cytokine-
responsive genes including, SOCS3 and to a lesser extent,responsive genes including, SOCS3 and to a lesser extent,
SOCS1. SOCS proteins inhibit or terminate JAK/STAT signalsSOCS1. SOCS proteins inhibit or terminate JAK/STAT signals
by binding to tyrosine-phosphorylated JAKs and/or cytokineby binding to tyrosine-phosphorylated JAKs and/or cytokine
receptors and targeting them for degradation.receptors and targeting them for degradation.
The STAT3signal can also be attenuated by PIAS3, a member ofThe STAT3signal can also be attenuated by PIAS3, a member of
the protein inhibitors of activated STATs (PIAS) family ofthe protein inhibitors of activated STATs (PIAS) family of
proteins. PIAS3 binds selectively to activated STAT3 dimersproteins. PIAS3 binds selectively to activated STAT3 dimers
and blocks their ability to activate gene transcription.and blocks their ability to activate gene transcription.

Regulation of the STAT3 signalRegulation of the STAT3 signal
transduction pathwaytransduction pathway

Regulation of intracellular Stat3Regulation of intracellular Stat3
signallingsignalling..

JAK/Stat pathway activation and inhibition.JAK/Stat pathway activation and inhibition.
Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left)Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left)
leading to sequential cell response.leading to sequential cell response.
The signaling process can be inhibited (right) byThe signaling process can be inhibited (right) by (1)(1) JAK degradation throughJAK degradation through
ubiquitin-proteasome system (Ub), (ubiquitin-proteasome system (Ub), (2)2) dephosphorylate in cytoplasmic PTP1Bdephosphorylate in cytoplasmic PTP1B
oror (3)(3) nuclear phosphatase (NPTP), or (nuclear phosphatase (NPTP), or (4)4) by blocking theby blocking the StatStat dimer formationdimer formation
Deng et al.,Deng et al., Current Cancer Drug TargetsCurrent Cancer Drug Targets, 2007, 7, 2007, 7,, 91-10791-107

Small Molecule Inhibitors of Stat3Small Molecule Inhibitors of Stat3
Signaling PathwaySignaling Pathway
Compelling evidence from mechanistic studies with antisense, RNACompelling evidence from mechanistic studies with antisense, RNA
interference (RNAi), peptides, and small molecular inhibitors indicateinterference (RNAi), peptides, and small molecular inhibitors indicate
that blocking Stat3 signaling can lead to successful suppression ofthat blocking Stat3 signaling can lead to successful suppression of
tumor cell growth and apoptosis.tumor cell growth and apoptosis.
Thus, Stat3 is an attractive molecular target for the development ofThus, Stat3 is an attractive molecular target for the development of
novel therapeutics.novel therapeutics.
These small molecular inhibitors, are divided into five classes ofThese small molecular inhibitors, are divided into five classes of
compounds.compounds.
They includeThey include
(1) Natural products and derivatives, such as curcumin,(1) Natural products and derivatives, such as curcumin,
resveratrol and others.resveratrol and others.
(2) Tyrphostins.(2) Tyrphostins.
(3) Patinum-containing complexes.(3) Patinum-containing complexes.
(5) Azaspiranes.(5) Azaspiranes.
Some compounds may have multiple targets including Stat3 protein.Some compounds may have multiple targets including Stat3 protein.
Stat3 targeted small molecules will be beneficial for databaseStat3 targeted small molecules will be beneficial for database
development and template design for future drug developmentdevelopment and template design for future drug development (( Deng,Deng,
etal.,etal., Current Cancer Drug TargetsCurrent Cancer Drug Targets, 2007, 7, 2007, 7,, 91-10791-107))

Effects of STAT3 Deﬁciency onEffects of STAT3 Deﬁciency on
Cellular FunctionCellular Function
Stuart et al.TStuart et al.The Journal of Immunology,he Journal of Immunology, 2009, 182: 21–282009, 182: 21–28

PsoriasisPsoriasis
Psoriasis is a chronic inflammatory skinPsoriasis is a chronic inflammatory skin
disease characterized by excessivedisease characterized by excessive
proliferation, abnormal differentiation ofproliferation, abnormal differentiation of
epidermal keratinocytes, vascularepidermal keratinocytes, vascular
proliferation, and leukocyte infiltration inproliferation, and leukocyte infiltration in
the dermis and epidermis .the dermis and epidermis .
It has been considered that psoriasisIt has been considered that psoriasis
results from complex, aberrantresults from complex, aberrant
relationships between the skin andrelationships between the skin and
immune systemimmune system as well as geneticas well as genetic
predisposition and environmental factorspredisposition and environmental factors

Combined data on psoriasis susceptibility loci
ND:not determinedND:not determined ((Pietrzak etal Folia Histochem Cytobiol. 2008:46(1): 12 (11-21)

Psoriasis Clinical PresentationPsoriasis Clinical Presentation

Clinical Manifestations ofClinical Manifestations of
PsoriasisPsoriasis

Histopathology of PsoriasisHistopathology of Psoriasis
Histology of healthy (A) and psoriatic (B) skin. Psoriatic skin shows epidermalHistology of healthy (A) and psoriatic (B) skin. Psoriatic skin shows epidermal
acantohosis, elongation of rete ridges (indicated by arrows) with reciprocalacantohosis, elongation of rete ridges (indicated by arrows) with reciprocal
elongation of intervening dermal papillae and inflammatory infiltrate (40Xelongation of intervening dermal papillae and inflammatory infiltrate (40X
magnificationmagnification).).

Stress Effects & PsoriasisStress Effects & Psoriasis
PathogenesisPathogenesis

Shared mechanisms betweenShared mechanisms between
psoriasis &cardiovascular systempsoriasis &cardiovascular system
In the lymph node, antigen-presenting cells (APCs)
activate naive T-cells to increase expression of
leukocyte- function-associated antigen-1 (LFA-1).
Activated T-cells migrate to blood vessel and adhere
to endothelium (and macrophages in case of
atherosclerosis).
After extravasation mediated by LFA-1 and
intercellular adhesion molecule-1 (ICAM-1) or CD2
and LFA-3, they interact with dendritic cells and
macrophages and keratinocytes in psoriasis but
smooth muscle cells in atherosclerosis.
These re-activated T-cells and macrophages secrete
chemokines and cytokines that contribute to the
inflammatory environment, resulting in the formation
of psoriatic plaque or atherosclerotic plaque.

Shared mechanisms betweenShared mechanisms between
psoriasis &cardiovascular systempsoriasis &cardiovascular system

Antigen-presenting cells (APCs) activate naive T cells within
the lymph node to increase expression of leucocyte-function-
associated antigen-1 (LFA-1); 2. Activated T cells migrate to
blood vessel.
Activated T cells adhere to endothelium;.
Activated T cells and macrophages collect on endothelium;.
Extravasation occurs mediated by LFA-1 and intercellular
adhesion molecule-1 (ICAM-1); 5. Activated T cell interacts with
macrophages, dendritic cells and smooth muscle cells ⁄
keratinocytes;.
Re-activated T cells and macrophages secrete chemokines and
cytokines that contribute to the inflammatory environment,
resulting in the formation of (a) psoriatic plaque, or (b)
atherosclerotic plaque;. Macrophages are transformed into
lipid-laden foam cells by uptake of oxidized LDL; ..
Formation of ‘fatty streaks’ in the subendothelium and,
eventually, atherosclerotic plaques.

Immunopathology of PsoriasisImmunopathology of Psoriasis
Psoriasis is initiated and maintained through a multifaceted interplayPsoriasis is initiated and maintained through a multifaceted interplay
between keratinocytes, blood vessels, gene expression, and thebetween keratinocytes, blood vessels, gene expression, and the
immune system.immune system.
The development of psoriatic plaque begins with antigen recognitionThe development of psoriatic plaque begins with antigen recognition
and uptake by antigen-presenting cells (APC)and uptake by antigen-presenting cells (APC)
In psoriasis the dendritic cells (DC) are the most common type ofIn psoriasis the dendritic cells (DC) are the most common type of
antigen-presenting cells.antigen-presenting cells.
Antigens are presented on the DC surface usually as MHC class IIAntigens are presented on the DC surface usually as MHC class II
molecules, which can be recognized by T cell receptor ofmolecules, which can be recognized by T cell receptor of CD4+ TCD4+ T
cells.cells.
In addition DCs can present antigens on MHC class I molecules,In addition DCs can present antigens on MHC class I molecules,
which lead to the activation ofwhich lead to the activation of CD8+ TCD8+ T cells. DCs also enhance thecells. DCs also enhance the
production of adhesion and co-stimulatory molecules to facilitate itsproduction of adhesion and co-stimulatory molecules to facilitate its
interaction with T cells (interaction with T cells (Sabat et al. 2007 Exp Dermatol 16:779-Sabat et al. 2007 Exp Dermatol 16:779-
798.798.).).

NaiveNaive T (CD4+ )cellsT (CD4+ )cells have to go through maturation in lymphatichave to go through maturation in lymphatic
tissues.tissues.
CD4+ TCD4+ T cells have a strong affinity to MHC II-peptide complex and theycells have a strong affinity to MHC II-peptide complex and they
stick together by forming an immunological synapsis.stick together by forming an immunological synapsis.
Interaction between ICAM-1, produced by DCs, and LFA-1, from TInteraction between ICAM-1, produced by DCs, and LFA-1, from T
cells, is one of the most important in order to facilitate the DC-T cellcells, is one of the most important in order to facilitate the DC-T cell
interaction.interaction.
Naive T cellsNaive T cells can mature either tocan mature either to Th1, Th2, Th17Th1, Th2, Th17 or regulatory T cellsor regulatory T cells
and subtype is guided by the selection of a soluble mediator presentand subtype is guided by the selection of a soluble mediator present
during the activation of naive T cells. After the activation,during the activation of naive T cells. After the activation, T cellsT cells
express cutaneous lymphocyte-associated antigen (express cutaneous lymphocyte-associated antigen (CLACLA), which), which
directsdirects T cellsT cells to inflamed skin.to inflamed skin.
P- and E-selectins expressed by endothelial cells are also importantP- and E-selectins expressed by endothelial cells are also important
for T cell skin homing (for T cell skin homing (Sabat et al. 2007 Exp Dermatol 16:779-798.Sabat et al. 2007 Exp Dermatol 16:779-798.).).

In inflamed skin,In inflamed skin, T cellsT cells enter the tissue and participate in theenter the tissue and participate in the
inflammation reaction.inflammation reaction.
Interaction between P- and E- selectins and CLA, as well as otherInteraction between P- and E- selectins and CLA, as well as other
selectin ligands, facilitate leukocytes rolling along the blood vesselselectin ligands, facilitate leukocytes rolling along the blood vessel
wall as they decrease the rolling velocity.wall as they decrease the rolling velocity.
Expressions of P- and E-selectins are upregulated in psoriatic skin,Expressions of P- and E-selectins are upregulated in psoriatic skin,
possibly stiffening the inflammation observed in psoriatic plaque.possibly stiffening the inflammation observed in psoriatic plaque.
T cellsT cells recognize chemokines secreted by the endothelial cells,recognize chemokines secreted by the endothelial cells,
become active and a tight adhesion, facilitated by integrinsbecome active and a tight adhesion, facilitated by integrins
produced byproduced by T cellsT cells and their ligands expressed by endothelial cells,and their ligands expressed by endothelial cells,
is formed between the cells.is formed between the cells.
The most important molecule in skin homing is LFA-1 binding toThe most important molecule in skin homing is LFA-1 binding to
ICAM-2. T cells probably enter the endothelial wall through poresICAM-2. T cells probably enter the endothelial wall through pores
formed between endothelial cells in an integrin-dependent processformed between endothelial cells in an integrin-dependent process
called diapedesiscalled diapedesis ((Sabat et al. 2007 Exp Dermatol 16:779-798.Sabat et al. 2007 Exp Dermatol 16:779-798.).).

In the skinIn the skin T cellsT cells are reactivated by different kinds of APCs, whichare reactivated by different kinds of APCs, which
also include keratinocytes. Interferon- (IFN-), produced by APCs,also include keratinocytes. Interferon- (IFN-), produced by APCs,
has an important role inhas an important role in T cellT cell reactivation and proliferation.reactivation and proliferation.
T cellsT cells in psoriatic skin have prolonged and increased IFN-in psoriatic skin have prolonged and increased IFN-
response when compared to healthy skin. Interferon- enhances INF-response when compared to healthy skin. Interferon- enhances INF-
expression inexpression in T cellsT cells..
Also cytokines produced by APCs, especiallyAlso cytokines produced by APCs, especially IL-23IL-23 andand IL-6IL-6, have, have
an important role in reactivation.an important role in reactivation.
After reactivationAfter reactivation T cellsT cells express a variety of cytokines.express a variety of cytokines.
T cell response leads to the activation of keratinocytes and theT cell response leads to the activation of keratinocytes and the
activation is carried out byactivation is carried out by Th17Th17 and different cytokines produced byand different cytokines produced by
macrophages, DCs and keratinocytes themselves.macrophages, DCs and keratinocytes themselves.
Keratinocyte activation leads to their increased proliferation andKeratinocyte activation leads to their increased proliferation and
alterations in the maturation process.alterations in the maturation process.
Activated keratinocytes produce a vast variety of mediators, whichActivated keratinocytes produce a vast variety of mediators, which
further promote immigration of inflammatory cells and inducefurther promote immigration of inflammatory cells and induce
angiogenesis, thus enhancing phenomena relevant for theangiogenesis, thus enhancing phenomena relevant for the
pathogenesis of psoriasis (pathogenesis of psoriasis (Sabat et al. 2007 Exp DermatolSabat et al. 2007 Exp Dermatol
16:779-798 &.16:779-798 &. Boehncke et alBoehncke et al JEADV 2010, 24 Suppl. 5, 2–24JEADV 2010, 24 Suppl. 5, 2–24))..

One previous psoriasis model demonstrated that overexpression ofOne previous psoriasis model demonstrated that overexpression of
the angiopoietin receptorthe angiopoietin receptor Tie2Tie2 in endothelial cells and keratinocytesin endothelial cells and keratinocytes
led to the development of a psoriasiform phenotype.led to the development of a psoriasiform phenotype.
Two new mouse models have been engineered wherebyTwo new mouse models have been engineered whereby Tie2Tie2
expression is confined to either endothelial cells or keratinocytes.expression is confined to either endothelial cells or keratinocytes.
Both lines of mice have significant increases in dermal vasculature butBoth lines of mice have significant increases in dermal vasculature but
only the KC-only the KC-Tie2-Tie2-overexpressing mice developed a cutaneousoverexpressing mice developed a cutaneous
psoriasiform phenotype.psoriasiform phenotype.
These mice spontaneously developed characteristic hallmarks ofThese mice spontaneously developed characteristic hallmarks of
human psoriasis, including extensive acanthosis, increases in dermalhuman psoriasis, including extensive acanthosis, increases in dermal
CD4+ T cells, infiltrating epidermal CD8+ T cells, dermal dendritic cellsCD4+ T cells, infiltrating epidermal CD8+ T cells, dermal dendritic cells
and macrophages, and increased expression of cytokines andand macrophages, and increased expression of cytokines and
chemokines associated with psoriasis, including interferon- , tumorchemokines associated with psoriasis, including interferon- , tumor
necrosis factor- , and interleukins 1 , 6, 12, 22, 23, and 17. Host-necrosis factor- , and interleukins 1 , 6, 12, 22, 23, and 17. Host-
defense molecules, cathelicidin, β-defensin, and S100A8/A9, were alsodefense molecules, cathelicidin, β-defensin, and S100A8/A9, were also
up-regulated in the hyperproliferative skin.up-regulated in the hyperproliferative skin.
Therefore, confiningTherefore, confining Tie2Tie2 overexpression solely to keratinocytesoverexpression solely to keratinocytes
results in a mouse model that meets the clinical, histological,results in a mouse model that meets the clinical, histological,
immunophenotypic, biochemical, and pharmacological criteriaimmunophenotypic, biochemical, and pharmacological criteria
required for an animal model of human psoriasis (required for an animal model of human psoriasis (Wolfram et al,Wolfram et al,AmericanAmerican
Journal of Pathology.Journal of Pathology. 2009 174:1443-1458 )2009 174:1443-1458 )..

Following a trigger or stimulus, dendritic cells and T cells are activated, leading to the formationFollowing a trigger or stimulus, dendritic cells and T cells are activated, leading to the formation
of an ‘immunological synapse’ that enhances theirof an ‘immunological synapse’ that enhances their interactions.interactions.
This ‘immunologic synapse’ results in the release of cytokines, chemokines and growthThis ‘immunologic synapse’ results in the release of cytokines, chemokines and growth
factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis.factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis.
Within the chronic psoriatic plaque, a vicious cycle of continuous T cell and dendritic cellWithin the chronic psoriatic plaque, a vicious cycle of continuous T cell and dendritic cell
activation is envisionedactivation is envisioned ((Nickoloff & Nestle :Nickoloff & Nestle : J Clin Invest 2004; 113: 1664–1675.).J Clin Invest 2004; 113: 1664–1675.).

Immunopathology of PsoriasisImmunopathology of Psoriasis((((Nickoloff &Nickoloff &
Nestle : J Clin Invest 2004; 113: 1664–1675.).Nestle : J Clin Invest 2004; 113: 1664–1675.).

Plasmacytoid predendritic cells (PDCs) &
Psoriasis Pathogenesis
Psoriasis is a chronic inflammatory skin disease that results from thePsoriasis is a chronic inflammatory skin disease that results from the
complex interplay between T cells, dendritic cells (DCs) andcomplex interplay between T cells, dendritic cells (DCs) and
keratinocyteskeratinocytes..
Plasmacytoid predendritic cells (PDCs), the natural interferon
(IFN)- –producing cells, infiltrate the skin of psoriatic patients and become
activated to produce IFN- early during disease formation.
In a xenograft model of human psoriasis, blocking IFN- signaling or inhibiting
the ability of PDCs to produce IFN- prevented the T cell–dependent
development of psoriasis.
Furthermore, IFN- reconstitution experiments demonstrated that PDC-derived
IFN- is essential to drive the development of psoriasis in vivo.
These findings uncover a novel innate immune pathway for triggering a
common human autoimmune disease and
suggest that PDCs and PDC-derived IFN- represent potential early targets for the
treatment of psoriasis (Nestle, et al 2005 JEM. 202, July 4:135–143).

PDCs are increased in the normal-appearingPDCs are increased in the normal-appearing
prepsoriatic skin of psoriasis patientsprepsoriatic skin of psoriasis patients
compared with the skin of healthy controls .compared with the skin of healthy controls .
This accumulation represents a conditioningThis accumulation represents a conditioning
factor for future flares of the disease.factor for future flares of the disease.
Through their ability to secrete IFN-Through their ability to secrete IFN- δδ inin
response to innate activation signals, PDCsresponse to innate activation signals, PDCs
in prepsoriatic skin determine the onset ofin prepsoriatic skin determine the onset of
local autoimmune inflammation leading tolocal autoimmune inflammation leading to
disease formation.disease formation.
Because injury to the skin is a well knownBecause injury to the skin is a well known
elicitation factor for psoriasis PDC activationelicitation factor for psoriasis PDC activation
may result from the release of skin-derivedmay result from the release of skin-derived
products on infectious or mechanical stressproducts on infectious or mechanical stress
(Nestle, et al 2005 JEM. 202, July 4:135–143).

In psoriatic skin,potential activation signalsIn psoriatic skin,potential activation signals
may include pathogen- or self derivedmay include pathogen- or self derived
single-stranded RNA.single-stranded RNA.
IFN-IFN-δδ is the molecular mediator of PDCis the molecular mediator of PDC
function in eliciting psoriasis.function in eliciting psoriasis.
PDC-derived IFN-PDC-derived IFN- δδ may drive themay drive the
“quiescent” autoimmune T cells in“quiescent” autoimmune T cells in
prepsoriatic skin into activated pathogenicprepsoriatic skin into activated pathogenic
effectors through the induction of dendreticeffectors through the induction of dendretic
cell activation/maturation(cell activation/maturation(Nestle, et al 2005
JEM. 202, July 4:135–143).
..

The presence of high levels of lesional IFN-The presence of high levels of lesional IFN- δδ mightmight
favor cross-presentation of sequestered tissue-favor cross-presentation of sequestered tissue-
specific autoantigens by myeloid DCs.specific autoantigens by myeloid DCs.
PDC derived IFN-PDC derived IFN- δδ may also enhance the survivalmay also enhance the survival
and expansionof T cells through the induction of IL-and expansionof T cells through the induction of IL-
15 or may act directly on T cells by promoting their15 or may act directly on T cells by promoting their
expression of T-bet and IL12-R 2 , thus potentiatingexpression of T-bet and IL12-R 2 , thus potentiating
the Th1 cell bias of pathogenic T cells in psoriasis..the Th1 cell bias of pathogenic T cells in psoriasis..
(Nestle, et al 2005 JEM. 202, July 4:135–143).

IFN-IFN- δδ is a master cytokine in psoriasis development.is a master cytokine in psoriasis development.
Production of IFN-Production of IFN- δδ is a tightly regulated, transient eventis a tightly regulated, transient event
occurring early during the development of psoriasis.occurring early during the development of psoriasis.
Production of IFN-Production of IFN- δδ in psoriatic skin seems to be confined toin psoriatic skin seems to be confined to
dermal PDCs.dermal PDCs.
Increasing evidence indicates that IFN-Increasing evidence indicates that IFN- δδ plays a pivotalplays a pivotal
role in the pathogenesis of other autoimmune disorders such asrole in the pathogenesis of other autoimmune disorders such as
SLE, insulin-dependent diabetes mellitus (IDDM), rheumatoidSLE, insulin-dependent diabetes mellitus (IDDM), rheumatoid
arthritis and psoriasis.arthritis and psoriasis.
As for psoriasis, IFN-As for psoriasis, IFN- δδ treatment for unrelated conditions cantreatment for unrelated conditions can
induce or exacerbate these autoimmune diseases.induce or exacerbate these autoimmune diseases.
PDCs and PDCderived IFN-PDCs and PDCderived IFN- δδ are being important upstreamare being important upstream
initiators of psoriasis developmentinitiators of psoriasis development (Nestle, et al 2005 JEM.
202, July 4:135–143).
..

Dermal Dendritic Cells inDermal Dendritic Cells in
PsoriasisPsoriasis
Many insults can lead to the activation of dermal
dendritic cells, a key initiating step in the
development of psoriasis in predisposed individuals.
Activated dendritic cells induce the proliferation of
autoreactive T cells within the dermis, inducing
production of IFN-γ and TNF-α, which in turn induces
the production chemotactic cytokines by epidermal
cells.
These chemotactic agents induce influx of
monocytes from the blood, which undergo
differentiation into macrophages and myeloid
dendritic cells.

PRR: pathogen-recognition receptor

STAT3 & Develoment of
Dendritic Cells (DC)
STAT3 activation is a checkpoint of
Flt3L(fim-like tyrosine kinase-3 ligand)-
regulated dendritic cell (DC)
development
Deletion of STAT3 causes a profound
deficency in the DC compartment and
abrogates the effect of Flt3L on DC
development (Laouar etal Immunity, 19, 903–912, 2003).

Macrophages in PsoriasisMacrophages in Psoriasis
The current classification of macrophages into classicallyThe current classification of macrophages into classically
activated (M1) and alternatively activated (M2) cells isactivated (M1) and alternatively activated (M2) cells is
parallel to the Th1/Th2 paradigm.parallel to the Th1/Th2 paradigm.
Classically activated (M1) macrophages are activated byClassically activated (M1) macrophages are activated by
IFN-γ,IFN-γ,
alone or in concert with microbial products (e.g. LPS) oralone or in concert with microbial products (e.g. LPS) or
cytokines (e.g.TNF) and have high capacity to presentcytokines (e.g.TNF) and have high capacity to present
antigen.antigen.
Alternatively activated (M2) macrophages are inducedAlternatively activated (M2) macrophages are induced
by IL-4 and IL-13 and promote Type 2 responses.by IL-4 and IL-13 and promote Type 2 responses.
CD163CD163, along with other macrophage markers such as, along with other macrophage markers such as
Factor XIIIA (FXIIIA), CD206/macrophage mannoseFactor XIIIA (FXIIIA), CD206/macrophage mannose
receptor (MMR), Macrophage Receptor with Collagenousreceptor (MMR), Macrophage Receptor with Collagenous
structure (MARCO) and Stabilin-1 are classified asstructure (MARCO) and Stabilin-1 are classified as
markers of alternatively activated macrophages.markers of alternatively activated macrophages.

Dermal macrophages are increased inDermal macrophages are increased in
psoriasis compared with normal skin and arepsoriasis compared with normal skin and are
identified by CD163identified by CD163 ..
Macrophages treated with IFN-γ show thatMacrophages treated with IFN-γ show that
many of the genes upregulated inmany of the genes upregulated in
macrophages are found in psoriasis,macrophages are found in psoriasis,
including STAT1, CXCL9, Mx1, and HLA-DR.including STAT1, CXCL9, Mx1, and HLA-DR.
CD163+ macrophages produce inflammatoryCD163+ macrophages produce inflammatory
molecules IL-23p19 and IL-12/23p40 as wellmolecules IL-23p19 and IL-12/23p40 as well
as tumor necrosis factor (TNF) and inducibleas tumor necrosis factor (TNF) and inducible
nitric oxide synthase (iNOS).nitric oxide synthase (iNOS).

CD163CD163 is a superior marker of macrophages, andis a superior marker of macrophages, and
identifies a subpopulation of “classically activated”identifies a subpopulation of “classically activated”
macrophages in psoriasis.macrophages in psoriasis.
Macrophages are likely to contribute to theMacrophages are likely to contribute to the
pathogenic inflammation in psoriasis, a prototypicalpathogenic inflammation in psoriasis, a prototypical
T helper 1T helper 1 ((Th1Th1) and) and Th17Th17 disease, by releasing keydisease, by releasing key
inflammatory productsinflammatory products
Dermal macrophages, once activated by T cell or
dendritic cell cytokines, they produce large
amounts of TNF-α, leading to the skin changes
observed in psoriasis. ((Journal of InvestigativeJournal of Investigative
DermatologyDermatology 130, 2412-2422 , 2010130, 2412-2422 , 2010).).

Stat 3 &MacrophagesStat 3 &Macrophages
Interleukin (IL) 10 is an immunosuppressive cytokineInterleukin (IL) 10 is an immunosuppressive cytokine
produced by T cells, B cells, dendritic cells&produced by T cells, B cells, dendritic cells&
monocytes/macrophages.monocytes/macrophages.
IL-10 acts by binding to the IL-10R1/IL-10R2 receptorIL-10 acts by binding to the IL-10R1/IL-10R2 receptor
complex that recruits Jak1 and Tyk2, and these thencomplex that recruits Jak1 and Tyk2, and these then
phosphorylate and activate the transcription factorphosphorylate and activate the transcription factor
Stat3.Stat3.
IL-10 itself may be controlled by Stat3 binding to aIL-10 itself may be controlled by Stat3 binding to a
cognate motif in the IL-10 promoter . These studiescognate motif in the IL-10 promoter . These studies
in human cells were supported by a report showingin human cells were supported by a report showing
the absence of IL-10 production in peritonealthe absence of IL-10 production in peritoneal
macrophages from animals that had a macrophage-macrophages from animals that had a macrophage-
specific knockout of thespecific knockout of the Stat3Stat3 gene .gene .
IL-10 will induce transactivation of the IL-10IL-10 will induce transactivation of the IL-10
promoter via Stat3 in primary human monocyte-promoter via Stat3 in primary human monocyte-
derived macrophagesderived macrophages

IL-10 is an important immunosuppressive cytokine that can
down-regulate expression of other cytokines and has been
shown to down-regulate itself.
Treatment of human monocyte-derived macrophages with IL-10
induces IL-10 mRNA in a dose- and time-dependent manner
Mutation of Stat 3 motif ablated IL-10 activation
Overexpression of a dominant-negative Stat3 protein will
prevent IL-10 induction, of IL-10 mRNA.
These data show that IL-10 induces IL-10 in monocyte-derived
macrophages in an autocrine manner via activation of the
transcription factor Stat3. (Staples et al 2007,The Journal of
Immunology, 178: 4779–4785.)

In mice, epidermis specific deletion of inhibitor of NF-In mice, epidermis specific deletion of inhibitor of NF-kkB (IB (IkkB)B)
kinase 2 (IKK2) results in a skin phenotype that mimics humankinase 2 (IKK2) results in a skin phenotype that mimics human
psoriasis in several aspects.psoriasis in several aspects.
Like psoriasis, this skin disease shows pronouncedLike psoriasis, this skin disease shows pronounced
improvement when mice are treated with a TNF-neutralizingimprovement when mice are treated with a TNF-neutralizing
agent.agent.
This phenotype does not depend on the presence ofThis phenotype does not depend on the presence of abab TT
lymphocytes. Elimination of skin macrophages bylymphocytes. Elimination of skin macrophages by
subcutaneous injection of clodronate liposomes wassubcutaneous injection of clodronate liposomes was
accompanied by inhibition of granulocyte migration into theaccompanied by inhibition of granulocyte migration into the
skin and resulted in a dramatic attenuation of psoriasis-likeskin and resulted in a dramatic attenuation of psoriasis-like
skin changes. The hyperproliferative, inflammatory skinskin changes. The hyperproliferative, inflammatory skin
disease in K14-Cre-IKK2fl/fl mice was a direct consequence ofdisease in K14-Cre-IKK2fl/fl mice was a direct consequence of
the presence of macrophages in the skin, as targeted deletionthe presence of macrophages in the skin, as targeted deletion
of CD18, which prevented accumulation of granulocytes butof CD18, which prevented accumulation of granulocytes but
not macrophages, did not lead to major changes in thenot macrophages, did not lead to major changes in the
phenotypephenotype ((Stratis etal.,Stratis etal., J. Clin. Invest.J. Clin. Invest. 116116:2094–2104 2006).,:2094–2104 2006).,..

Bidirectional flow of ‘information’ and cells in aBidirectional flow of ‘information’ and cells in a
mature psoriasis lesionmature psoriasis lesion
There is close interdependence of theThere is close interdependence of the
epidermis and dermal inflammatory infiltrate,epidermis and dermal inflammatory infiltrate,
as well as a balance between the innate andas well as a balance between the innate and
acquired immune systems.acquired immune systems.
Chemokines produced by keratinocytes inChemokines produced by keratinocytes in
the epidermis act on both the innate andthe epidermis act on both the innate and
acquired immune systems, stimulating DCs,acquired immune systems, stimulating DCs,
neutrophils and other innate mediators asneutrophils and other innate mediators as
well as T cells.well as T cells.
Keratinocytes also release cytokines andKeratinocytes also release cytokines and
growth factors, leading to altered genegrowth factors, leading to altered gene
expression and regenerative hyperplasia.expression and regenerative hyperplasia.

Bidirectional flow of ‘information’ and cells in aBidirectional flow of ‘information’ and cells in a
mature psoriasis lesionmature psoriasis lesion
Immune-system-derived cytokines, in turn,Immune-system-derived cytokines, in turn,
act on keratinocytes to either induceact on keratinocytes to either induce
inflammatory genes or increase proliferation.inflammatory genes or increase proliferation.
Meanwhile, in the lymphoid-like tissue of theMeanwhile, in the lymphoid-like tissue of the
psoriatic dermis, molecules of the innate andpsoriatic dermis, molecules of the innate and
acquired immune systems also interact.acquired immune systems also interact.
The genetic underpinnings of psoriasis areThe genetic underpinnings of psoriasis are
known to be complex, with ten or moreknown to be complex, with ten or more
susceptibility loci, and these probablysusceptibility loci, and these probably
interact with various environmental factorsinteract with various environmental factors
that act on the skin and/or immune systemthat act on the skin and/or immune system..

Immunocompetent CellsImmunocompetent Cells
Interactions in PsoriasisInteractions in Psoriasis

Keratinocytes cross talks amongKeratinocytes cross talks among
immune cellsimmune cells in psoriasisin psoriasis

Cytokines in PsoriasisCytokines in Psoriasis

Psoriasis: Evidence ofPsoriasis: Evidence of
T-Cell MediationT-Cell Mediation
Early cells in psoriatic lesionsEarly cells in psoriatic lesions
Cyclosporine, anti-CD4 monoclonalCyclosporine, anti-CD4 monoclonal
antibodies are used as treatmentantibodies are used as treatment
Blocking T cell:APC 2nd signalBlocking T cell:APC 2nd signal
prevents psoriatic lesionprevents psoriatic lesion
Psoriasis altered in HIV infectionPsoriasis altered in HIV infection
Streptococcal superantigens canStreptococcal superantigens can
induce psoriasisinduce psoriasis

T-Cell in PsoriasisT-Cell in Psoriasis
The pathogenesis of psoriasis is a multistepThe pathogenesis of psoriasis is a multistep
process, and an array ofprocess, and an array of cytokinescytokines has anhas an
impressive role in these processes .impressive role in these processes .
IL-2IL-2 andand IFN-γIFN-γ are two important cytokines,are two important cytokines,
which secreted uponwhich secreted upon Th1Th1 activation.activation.
These cytokines activate different signalThese cytokines activate different signal
transducers and augment transcription of atransducers and augment transcription of a
large group of immune related genes andlarge group of immune related genes and
may contribute to the overall pathogenicmay contribute to the overall pathogenic
process (process (Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91))

T-Cell in PsoriasisT-Cell in Psoriasis
TheThe Th1Th1 character of psoriasis is supported by thecharacter of psoriasis is supported by the
development of skin lesions in quiescent patients treateddevelopment of skin lesions in quiescent patients treated
withwith IL-2IL-2 for cancer therapy.for cancer therapy.
Conversely, a therapeutic effect, accompanied by a shiftConversely, a therapeutic effect, accompanied by a shift
toward Th2 cytokine expression patterns, is seen intoward Th2 cytokine expression patterns, is seen in
psoriasis patients following administration of thepsoriasis patients following administration of the Th2Th2
cytokine,cytokine, IL-10IL-10..
T cellsT cells cloned from psoriatic skin can variously producecloned from psoriatic skin can variously produce
IFNIFN-,-, TGFTGF-,-, IL-2IL-2,, IL-3IL-3,, IL-6IL-6,, IL-8IL-8, and, and GM-CSFGM-CSF, although, although
none of these are singly responsible fornone of these are singly responsible for T cellT cell stimulationstimulation
of keratinocyte growth, which appears to involveof keratinocyte growth, which appears to involve IFNIFN- inin
concert with other cytokines .concert with other cytokines .
IL-7IL-7 ,, produced by both T cells & keratinocytes, is alsoproduced by both T cells & keratinocytes, is also
present at elevated levels in lesional psoriatic comparedpresent at elevated levels in lesional psoriatic compared
with nonlesional and normal skinwith nonlesional and normal skin (( Mollison et alMollison et al
Journal of Investigative DermatologyJournal of Investigative Dermatology ,1999, 112: 729–,1999, 112: 729–
738;) .738;) .

Serum cytokine levels of psoriatic patients andSerum cytokine levels of psoriatic patients and
controlscontrols ((Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91))

Serum levels of s IL - 2R in patients with psoriasis vulgarisSerum levels of s IL - 2R in patients with psoriasis vulgaris
compared to healthy controlscompared to healthy controls ((Halla M. Ragab et alHalla M. Ragab et al J. ofJ. of
American Science 2010;6(10):423-429American Science 2010;6(10):423-429))

Serum levels of IL - 6 in patients with psoriasisSerum levels of IL - 6 in patients with psoriasis
vulgaris compared to healthy controlsvulgaris compared to healthy controls ((Halla M.Halla M.
Ragab et alRagab et al J. of American Science 2010;6(10):423-J. of American Science 2010;6(10):423-
429429))

Serum IL17 & IL22 in psoriasisSerum IL17 & IL22 in psoriasis
Inas Almakhzangy & A. Gaballa Egyptian Dermatology Online Journal 5 (1): 4, 2009

T Helper 1 versus 2 in psoriasisT Helper 1 versus 2 in psoriasis
Psoriasis is an inflammatory skin disorder characterized by increasedPsoriasis is an inflammatory skin disorder characterized by increased
activation of CD4+ T lymphocytes, and systemic and localactivation of CD4+ T lymphocytes, and systemic and local
overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-
2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha,2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha,
indicating that immunopathogenesis of the disease is T helper 1 (Th1)indicating that immunopathogenesis of the disease is T helper 1 (Th1)
mediated.mediated.
T helper cell precursors (Thp) can be skewed towards mutuallyT helper cell precursors (Thp) can be skewed towards mutually
exclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes onexclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on
the basis of the cytokine environment.the basis of the cytokine environment.
Several studies suggest a pivotal role of bacterial superantigens in theSeveral studies suggest a pivotal role of bacterial superantigens in the
initiation and/or exacerbation of this illness. In contrast to controls,initiation and/or exacerbation of this illness. In contrast to controls,
psoriasis patients in the early course of disease were characterized bypsoriasis patients in the early course of disease were characterized by
significantly increased expression of the pro-inflammatory cytokinesignificantly increased expression of the pro-inflammatory cytokine
IFN-, whilst a shift towards IL-10 secretion (Th2 response) wasIFN-, whilst a shift towards IL-10 secretion (Th2 response) was
observed in those presenting with increased duration of disease.observed in those presenting with increased duration of disease.
PDC derived IFN-PDC derived IFN- δδ may also enhance the survival and expansion of Tmay also enhance the survival and expansion of T
cells through the induction of IL-15 or may act directly on T cells bycells through the induction of IL-15 or may act directly on T cells by
promoting their expression of T-bet and IL12-R 2 , thus potentiatingpromoting their expression of T-bet and IL12-R 2 , thus potentiating
the Th1 cell bias of pathogenic T cells in psoriasis..the Th1 cell bias of pathogenic T cells in psoriasis..
These observations suggest a possible shift from a Th1 to a Th2These observations suggest a possible shift from a Th1 to a Th2
cytokine response with superantigen-associated progression for thecytokine response with superantigen-associated progression for the
duration of psoriasis, perhaps as an adaptive process by the immuneduration of psoriasis, perhaps as an adaptive process by the immune
system in an attempt to downregulate abnormal inflammatory Th1system in an attempt to downregulate abnormal inflammatory Th1
immune responsesimmune responses ((Jain etal 2009 J Med Microbiol 58 :180-184).Jain etal 2009 J Med Microbiol 58 :180-184).

PSORIASIS IS aPSORIASIS IS aTH17TH17
DISEASE :A HypothesisDISEASE :A Hypothesis
An initiating event such as trauma or skin surface microbesAn initiating event such as trauma or skin surface microbes
triggerstriggers IL-23IL-23 production by keratinocytes and residentproduction by keratinocytes and resident
dendritic cells, which in turn stimulates proliferation of CCR4+dendritic cells, which in turn stimulates proliferation of CCR4+
and CCR6+and CCR6+Th17Th17 cells found within skin.cells found within skin.
These activatedThese activated Th17Th17 cells secrete Th17 cytokines includingcells secrete Th17 cytokines including IL-IL-
2222 andand IL-17AIL-17A, which cause keratinocyte growth and activation,, which cause keratinocyte growth and activation,
respectively.respectively.
Th17Th17 cytokines also induce CCL20 production bycytokines also induce CCL20 production by
keratinocytes, which fosters additional chemotaxis of CCR6+keratinocytes, which fosters additional chemotaxis of CCR6+
++Th17Th17 cells and CCR6 dendritic cells from blood into skin.cells and CCR6 dendritic cells from blood into skin.
Cytokines released by these newly recruited cells maintainCytokines released by these newly recruited cells maintain
psoriaticpsoriatic inflammation (inflammation (Fitch, etal., Current RheumatologyFitch, etal., Current Rheumatology
Reports 2007, 9:461–467Reports 2007, 9:461–467))

CD4+ and CD8+ T-cell clones derived fromCD4+ and CD8+ T-cell clones derived from
lesional psoriatic skin in humans expressedlesional psoriatic skin in humans expressed
IL-17IL-17, irrespective of their IFN-γ or IL-4, irrespective of their IFN-γ or IL-4
production.production.
IL-17IL-17 expression is detectable in biopsiesexpression is detectable in biopsies
from lesional psoriatic skin, but not infrom lesional psoriatic skin, but not in
nonlesional control biopsiesnonlesional control biopsies
Th17Th17 cells are present in the inflammatorycells are present in the inflammatory
infiltrate in psoriatic plaques to induceinfiltrate in psoriatic plaques to induce
enhancement of neutrophil chemotaxisenhancement of neutrophil chemotaxis

The expression of IL-23 is highly enhanced inThe expression of IL-23 is highly enhanced in
lesional psoriatic skin .lesional psoriatic skin .
This IL 23, aThis IL 23, a Th17Th17-inducing factor, is-inducing factor, is
produced by keratinocytes, Langerhans cellsproduced by keratinocytes, Langerhans cells
and macrophages.and macrophages.
The enhanced expression of both IL-23 andThe enhanced expression of both IL-23 and
IL-17 within psoriatic lesions indicates thatIL-17 within psoriatic lesions indicates that
the IL-23/IL-17 cytokine axis is fullythe IL-23/IL-17 cytokine axis is fully
operational in the inflamed skin.operational in the inflamed skin.

IL-22, which mediates acanthosis, isIL-22, which mediates acanthosis, is
preferentially expressed bypreferentially expressed by Th17Th17 cells and,cells and,
likelike IL-17IL-17, can be induced by IL-23., can be induced by IL-23.
The production ofThe production of IL-17IL-17 and IL-22, however,and IL-22, however,
appears to be differentially regulated.appears to be differentially regulated.
Whereas IL-6 alone can induce IL-22, but notWhereas IL-6 alone can induce IL-22, but not
IL-17IL-17, the additional presence of TGFß dose, the additional presence of TGFß dose
dependently inhibits the expression of IL-dependently inhibits the expression of IL-
22, while it promotes IL-17 production22, while it promotes IL-17 production

STAT3 REGULATION of CYTOKINE-STAT3 REGULATION of CYTOKINE-
MEDIATED GENERATION of TH 17MEDIATED GENERATION of TH 17
IL-6 functions to up-regulate IL-23R and that IL-23 synergizedIL-6 functions to up-regulate IL-23R and that IL-23 synergized
with IL-6 in promoting THi (with IL-6 in promoting THi (TH17TH17)generation.)generation.
STAT3, activated by both IL-6 and IL-23, plays a critical role inSTAT3, activated by both IL-6 and IL-23, plays a critical role in
THi development.THi development.
A hyperactive form of STAT3 promoted THi development,A hyperactive form of STAT3 promoted THi development,
whereas this differentiation process was greatly impaired inwhereas this differentiation process was greatly impaired in
STAT3-deficient T cells.STAT3-deficient T cells.
Moreover, STAT3 regulated the expression of retinoic acidMoreover, STAT3 regulated the expression of retinoic acid
receptor-related orphan receptor IL-17 -T (RORt), a THi-specificreceptor-related orphan receptor IL-17 -T (RORt), a THi-specific
transcriptional regulator.transcriptional regulator.
STAT3 deficiency impaired ROR t expression and led to elevatedSTAT3 deficiency impaired ROR t expression and led to elevated
expression of T-box expressed in T cells (T-bet) and Forkheadexpression of T-box expressed in T cells (T-bet) and Forkhead
box P3 (Foxp3).box P3 (Foxp3).
There is a pathway whereby cytokines regulate THiThere is a pathway whereby cytokines regulate THi
differentiation through a selective STAT transcription factor thatdifferentiation through a selective STAT transcription factor that
functions to regulate lineage-specific gene expression (functions to regulate lineage-specific gene expression (Yang etYang et
al.,2007 J.Biol Chem.,282,13:9358al.,2007 J.Biol Chem.,282,13:9358& Egwuagu :Cytokine 47 (2009) 149–156& Egwuagu :Cytokine 47 (2009) 149–156))..

Keratinocytes cross talks withKeratinocytes cross talks with
immune cellsimmune cells in psoriasisin psoriasis

Through the production of pro-
inflammatory type 1 cytokines (TNF-α,
IFN-γ), lymphocyte activation leads to a
cascade of recruitment and/or
activation of many other cell
populations, including alterations of
keratinocytic proliferation and
differentiation

T HelperT Helper 1717 ActivationActivation
Mechanisms in PsoriasisMechanisms in Psoriasis
(Fitch, etal., Current Rheumatology Reports 2007, 9:461–(Fitch, etal., Current Rheumatology Reports 2007, 9:461–
467467))

TH17 cells: effector cytokines and their function.
Th17 cells characterized by production of IL-17A, IL-17F, IL-22, and IL-
21.
Both IL-22 and IL-21 are not the exclusive cytokines produced byTh17
cells. IL-17A and IL-17F mediate tissue damages during organ
specific autoimmunity via variety of mechanism including the
activation of matrix metalloproteinases and recruitment o f
neutrophils.
IL-22 induces skin inflammation. IL-21 mediates amplification of T
helper 17 pathway.

Proinflammatory Effects ofProinflammatory Effects of
IL17IL17

The interleukin (IL)-23/Th17 axis in theThe interleukin (IL)-23/Th17 axis in the
immunopathogenesis of psoriasisimmunopathogenesis of psoriasis
T helper 17 (Th17) cells interact with skin-resident cells, contributing to the psoriaticT helper 17 (Th17) cells interact with skin-resident cells, contributing to the psoriatic
disease phenotype, characterized by scaly plaques and thickened epidermis (acanthosis),disease phenotype, characterized by scaly plaques and thickened epidermis (acanthosis),
with elongated rete ridges and hyperproliferative keratinocytes (KCs) retaining the nucleuswith elongated rete ridges and hyperproliferative keratinocytes (KCs) retaining the nucleus
in the stratum corneum (parakeratosis), as well as dermal inflammatory cell infiltrate.in the stratum corneum (parakeratosis), as well as dermal inflammatory cell infiltrate.
IL-23 secreted by dermal dendritic cells (DCs) is able to induce Th17 cell activation withIL-23 secreted by dermal dendritic cells (DCs) is able to induce Th17 cell activation with
production of pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFN-γ.production of pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFN-γ.
These cytokines act on KCs, inducing epidermal hyperplasia and KC activation. ActivatedThese cytokines act on KCs, inducing epidermal hyperplasia and KC activation. Activated
KCs produce pro-inflammatory mediators, includingKCs produce pro-inflammatory mediators, including chemokines (chemokines (These include aThese include a
broad spectrum of related mediators (up to 50 molecules havebroad spectrum of related mediators (up to 50 molecules have
been identi®ed),6 known primarily for inducing chemotaxis ofbeen identi®ed),6 known primarily for inducing chemotaxis of
various leukocyte subsets. On the basis of the presence orvarious leukocyte subsets. On the basis of the presence or
absence of a single amino acid between two cysteine residues,absence of a single amino acid between two cysteine residues,
these cytokines have been divided into two major classes,these cytokines have been divided into two major classes,
namely C-X-C and C-Cnamely C-X-C and C-C).)., members of the S100 family, pro-inflammatory, members of the S100 family, pro-inflammatory
cytokines and antimicrobial peptides. In particular, CCL20 is able to recruit more CCR6+cytokines and antimicrobial peptides. In particular, CCL20 is able to recruit more CCR6+
Th17 cells.Th17 cells.
Moreover, KCs might produce IL-23, which could mediate crosstalk with Th17 cells inMoreover, KCs might produce IL-23, which could mediate crosstalk with Th17 cells in
synergy with IL-23 produced by dermal DCs, thus further sustaining and amplifying skinsynergy with IL-23 produced by dermal DCs, thus further sustaining and amplifying skin
inflammation.inflammation.

Adapted from Iwakura & Ishigame, J Clin Invest 116:1218-1222 (2006)
Roles of IL-23 on T Helper 17 cellsRoles of IL-23 on T Helper 17 cells
in Chronic Inflammation in Psoriasisin Chronic Inflammation in Psoriasis
Dendritic
cell
Macrophage
IL-23
IL-12
Th1
Th17
IFNγ
IL-1, IL-6
TNF
Inflammatory
response
Endothelial cells
Stromal cells
Epithelial cells
Fibroblasts
Macrophage
IL-17, IL-6 IL-1
IL-6
IL-8
TNF
IL-12R
IL-23R
IL-23R

Roles of IL-23 on T Helper 17 cellsRoles of IL-23 on T Helper 17 cells
in Chronic Inflammation in Psoriasisin Chronic Inflammation in Psoriasis
There is an important role for IL-23-inducedThere is an important role for IL-23-induced Th17Th17
cells and thecells and the Th17Th17-derived cytokines-derived cytokines IL-17IL-17 and IL-22and IL-22
in the immunopathogenetic mechanisms underlyingin the immunopathogenetic mechanisms underlying
psoriasis.psoriasis.
A clinical improvement in most psoriasis patientsA clinical improvement in most psoriasis patients
was observed after therapy with blockingwas observed after therapy with blocking
monoclonal antibodies against p40, the sharedmonoclonal antibodies against p40, the shared
subunit of the heterodimeric cytokines IL-12 and IL-subunit of the heterodimeric cytokines IL-12 and IL-
23.23.
The finding that this treatment causes aThe finding that this treatment causes a
downregulation of p40 and IL-23 p19, but not of IL-12downregulation of p40 and IL-23 p19, but not of IL-12
p35 in psoriatic skin lesions suggests thatp35 in psoriatic skin lesions suggests that
interference with IL-23 rather than IL-12 activity isinterference with IL-23 rather than IL-12 activity is
responsible for this clinical improvementresponsible for this clinical improvement..

Interleukin-23 (IL-23Interleukin-23 (IL-23) helps to maintain the lesion by leading to the) helps to maintain the lesion by leading to the
development ofdevelopment of Th17Th17 cells.cells.
These in turn produce necrosis factor-alpha (TNF-a), IThese in turn produce necrosis factor-alpha (TNF-a), IL-17L-17 andand IL-22.IL-22.
IL-22IL-22 is believed to drive many of the epidermal changes inis believed to drive many of the epidermal changes in psoriasispsoriasis..
Many autoimmune diseases, includingMany autoimmune diseases, including psoriasispsoriasis, are characterized by high, are characterized by high
levels oflevels of Th17Th17..
Journal of Investigative Dermatology 2009;129:1339–1350Journal of Investigative Dermatology 2009;129:1339–1350..

Genetic PolymorphismGenetic Polymorphism
Certain genetic changes in IL-12/23p40 andCertain genetic changes in IL-12/23p40 and
IL-23R will lead to enhanced IL-23 productionIL-23R will lead to enhanced IL-23 production
and IL-23 receptor-mediated signaling andand IL-23 receptor-mediated signaling and
thus be correlative with psoriasisthus be correlative with psoriasis
susceptibility in humans.susceptibility in humans.
Certain IL-12/23p40 and IL-23RCertain IL-12/23p40 and IL-23R
polymorphisms correlate with certainpolymorphisms correlate with certain
disease presentations (e.g., guttate vs.disease presentations (e.g., guttate vs.
pustular psoriasis) or with severity ofpustular psoriasis) or with severity of
diseasedisease ..
((BlauveltBlauvelt J Invest Dermatol. 2008 ; 128(5):J Invest Dermatol. 2008 ; 128(5):
1064–10671064–1067).).

Schematic of the related heterodimers IL-23 and IL-12 and their relatedSchematic of the related heterodimers IL-23 and IL-12 and their related
heterodimeric cytokine receptors, indicating (heterodimeric cytokine receptors, indicating (in red circlesin red circles) the) the
subunits where polymorphisms in genes encoding these proteinssubunits where polymorphisms in genes encoding these proteins
have been linked to development of psoriasishave been linked to development of psoriasis ((BlauveltBlauvelt J InvestJ Invest
Dermatol. 2008 128(5): 1064–1067Dermatol. 2008 128(5): 1064–1067).).

Stat3 links activated keratinocytes andStat3 links activated keratinocytes and
immunocytes required for developmentimmunocytes required for development
of psoriasisof psoriasis
Epidermal keratinocytes in psoriatic lesions are characterizedEpidermal keratinocytes in psoriatic lesions are characterized
by activated Stat3.by activated Stat3.
Transgenic mice with keratinocytes expressing a constitutivelyTransgenic mice with keratinocytes expressing a constitutively
active Stat3 (active Stat3 (K5.Stat3C miceK5.Stat3C mice) develop a skin phenotype either) develop a skin phenotype either
spontaneously, or in response to wounding, that closelyspontaneously, or in response to wounding, that closely
resembles psoriasis.resembles psoriasis.
Keratinocytes fromKeratinocytes from K5.Stat3C miceK5.Stat3C mice show upregulation ofshow upregulation of
several molecules linked to the pathogenesis of psoriasis.several molecules linked to the pathogenesis of psoriasis.
In addition, the development of psoriatic lesions inIn addition, the development of psoriatic lesions in K5.Stat3CK5.Stat3C
mice requires cooperation between Stat3 activation inmice requires cooperation between Stat3 activation in
keratinocytes and activated T cells.keratinocytes and activated T cells.
Finally, abrogation of Stat3 function by a decoy oligonucleotideFinally, abrogation of Stat3 function by a decoy oligonucleotide
inhibits the onset and reverses established psoriatic lesions ininhibits the onset and reverses established psoriatic lesions in
K5.Stat3C mice.K5.Stat3C mice.
Thus, targeting Stat3Thus, targeting Stat3 may be potentially therapeutic in themay be potentially therapeutic in the
treatment of psoriasis.treatment of psoriasis.

Experimental Models ofExperimental Models of
PsoriasisPsoriasis
An interesting transgenic mouse model for psoriasis is transgenicAn interesting transgenic mouse model for psoriasis is transgenic
mouse with constitutively active Stat3 overexpression.mouse with constitutively active Stat3 overexpression.
Stat3, participates in cell proliferation, apoptosis, cell differentiationStat3, participates in cell proliferation, apoptosis, cell differentiation
and other important biological functionsand other important biological functions
In addition, its expression is elevated in psoriasis and in lesionalIn addition, its expression is elevated in psoriasis and in lesional
keratinocytes, particularly in the nuclei of keratinocytes .keratinocytes, particularly in the nuclei of keratinocytes .
Stat3 is activated by many different cytokines, including membersStat3 is activated by many different cytokines, including members
of IL-20 subfamily cytokines, namely IL-19, IL-20, IL-22 and IL-24,of IL-20 subfamily cytokines, namely IL-19, IL-20, IL-22 and IL-24,
which are all upregulated in psoriatic skin .which are all upregulated in psoriatic skin .
Of these, IL-22 is produced by Th17 lymphocytes, in contrast toOf these, IL-22 is produced by Th17 lymphocytes, in contrast to
the other related cytokines, and its production is induced by IL-23.the other related cytokines, and its production is induced by IL-23.
Overexpression of IL-23 is profound in lesional psoriatic skin andOverexpression of IL-23 is profound in lesional psoriatic skin and
Stat3 activation via IL-22 seems to be important in the IL-23-inducedStat3 activation via IL-22 seems to be important in the IL-23-induced
epidermal acanthosis relevant in the pathogenesis of psoriasisepidermal acanthosis relevant in the pathogenesis of psoriasis
((Zhang et al 2007 J Invest Dermatol, 27:2544-2551 andZhang et al 2007 J Invest Dermatol, 27:2544-2551 and
DANILENKO,2008 Vet Pathol 45:563–575)

PsoriasisPsoriasis
The scientists transplanted skin from their STAT3 miceThe scientists transplanted skin from their STAT3 mice
to a mouse that produces no T cells, a key component ofto a mouse that produces no T cells, a key component of
the immune system that is believed to be necessary forthe immune system that is believed to be necessary for
development of psoriasis.development of psoriasis.
The transplanted skin did not initially develop psoriasisThe transplanted skin did not initially develop psoriasis
lesions.lesions.
However, when the scientists injected activated T cellsHowever, when the scientists injected activated T cells
into the skin grafts on T cell-free mice, the mice theninto the skin grafts on T cell-free mice, the mice then
developed psoriasis following mild injury.developed psoriasis following mild injury.
"This experiment showed it is necessary to have both"This experiment showed it is necessary to have both
activated STAT3 in keratinocytes and infiltrating,activated STAT3 in keratinocytes and infiltrating,
activated T cells to develop psoriasis. "activated T cells to develop psoriasis. "Neither isNeither is
sufficient alone."sufficient alone." ((DiGiovanni’s et alDiGiovanni’s et al, the Journal Nature, the Journal Nature
Medicine ,Jan.2005Medicine ,Jan.2005))

PsoriasisPsoriasis
Constitutive activation of Stat3Constitutive activation of Stat3
micemice ((K5.Stat3C miceK5.Stat3C mice)) increased theincreased the
sensitivity of the epidermis tosensitivity of the epidermis to
external stimuli, leading to aexternal stimuli, leading to a
psoriatic phenotype, similar topsoriatic phenotype, similar to
the clinical Koebnerthe clinical Koebner
phenomenon(phenomenon(SanoSano etal., Journal ofetal., Journal of
Dermatological Science (2008) 50, 1—14Dermatological Science (2008) 50, 1—14))..

Up-regulated molecules in keratinocytes ofUp-regulated molecules in keratinocytes of
K5.Stat3CK5.Stat3C micemice
(Sano(Sano etal., Journal of Dermatological Science (2008) 50, 1—etal., Journal of Dermatological Science (2008) 50, 1—
1414))

Blocking the function ofBlocking the function of STAT3STAT3 using antisense oligo-using antisense oligo-
nucleotides inhibited the onset of, and reversed,nucleotides inhibited the onset of, and reversed,
established psoriatic lesionsestablished psoriatic lesions..
Further analysis revealed a dual requirement of bothFurther analysis revealed a dual requirement of both
activated STAT3 in keratinocytes as well as in T cells,activated STAT3 in keratinocytes as well as in T cells,
indicating that the pathogenesis of psoriasis is rooted in aindicating that the pathogenesis of psoriasis is rooted in a
co-operative process involving STAT3-regulated genes inco-operative process involving STAT3-regulated genes in
both skin cells and the immune system .both skin cells and the immune system .
Phosphatyrosyl peptides block STAT3-mediated DNAPhosphatyrosyl peptides block STAT3-mediated DNA
binding activity, gene regulation and cell transformation.binding activity, gene regulation and cell transformation.
((VaradwajVaradwaj et al 2010et al 2010 EgyptianEgyptian
Dermatology Online Journal 6 (1Dermatology Online Journal 6 (1)) ))

Development of psoriasis following woundDevelopment of psoriasis following wound
healinghealing..
((A)Psoriasis upon burn scar in a 74-year-old woman. (B) EpidermalA)Psoriasis upon burn scar in a 74-year-old woman. (B) Epidermal
keratinocytes of psoriatic lesions show activated Stat3. Nuclei of the lesionalkeratinocytes of psoriatic lesions show activated Stat3. Nuclei of the lesional
keratinocytes are positive for Stat3, suggesting activated status of Stat3keratinocytes are positive for Stat3, suggesting activated status of Stat3))
SanoSano etal., Journal of Dermatological Science (2008) 50, 1—14etal., Journal of Dermatological Science (2008) 50, 1—14))

Psoriatic lesions of K5.Stat3C micePsoriatic lesions of K5.Stat3C mice
((A)Psoriasis lesions and its histology (H and E staining,A)Psoriasis lesions and its histology (H and E staining,
(B).(B). (Sano(Sano etal., Journal of Dermatological Scienceetal., Journal of Dermatological Science
(2008) 50, 1—14(2008) 50, 1—14))

A Tender Piece of InformationA Tender Piece of Information

Do Other Therapies Work Within ThisDo Other Therapies Work Within This
Framework?Framework?
Anti–T-cell agents could affectAnti–T-cell agents could affect Th17Th17
cells as they would other T cells, butcells as they would other T cells, but
this needs to be clarifiedthis needs to be clarified
Anti-TNFAnti-TNF agents could decreaseagents could decrease
activity ofactivity of Th1Th17 cells or work directly7 cells or work directly
on keratinocyte responseson keratinocyte responses

Studies on Stat 3 in PsoriasisStudies on Stat 3 in Psoriasis

Stat 3 in PsoriasisStat 3 in Psoriasis

Oxidative stress in the
pathogenesis of psoriasis

Nitric oxide(NO) in the skin
NO is produced from L-arginine in an
enzyme-catalyzed reaction
The family of NO synthases (NOS) consists
of constitutive enzymes such as the neural
and endothelial NOS (nNOS and eNOS,
respectively) and the inducible nitric oxide
synthase (iNOS).
Induction of iNOS expression by
inflammatory cytokines and/or bacterial
products results in the production of large
amounts of NO

Psoriasis &inducible nitric oxidePsoriasis &inducible nitric oxide
synthase (iNOS).
Psoriasis Human iNOS mRNA and IL-8 mRNA colocalize in thePsoriasis Human iNOS mRNA and IL-8 mRNA colocalize in the
epidermal keratinocytes in psoriatic skin lesions.epidermal keratinocytes in psoriatic skin lesions.
Human Epidermal keratinocyte express iNOS in skin lesions ofHuman Epidermal keratinocyte express iNOS in skin lesions of
psoriasis vulgaris.psoriasis vulgaris.
Human Overexpression of iNOS mRNA in psoriatic lesions.Human Overexpression of iNOS mRNA in psoriatic lesions.
Human NO release accounts for the reduced incidence ofHuman NO release accounts for the reduced incidence of
cutaneous infections in psoriasis.cutaneous infections in psoriasis.
Human Tenfold increase of NO production in psoriasis, asHuman Tenfold increase of NO production in psoriasis, as
measured on the skin surface.measured on the skin surface.
Localization of iNOS expression in psoriasis: papillary dermisLocalization of iNOS expression in psoriasis: papillary dermis
and focally in keratinocytes.and focally in keratinocytes.
iNOS expression correlates with proliferation andiNOS expression correlates with proliferation and
inflammatory infiltratesinflammatory infiltrates ((Vira´etal., Experimental Dermatology
2002: 11: 189–202)

Oxidative stress in the
pathogenesis of psoriasis
The positive feedback loop involved in
psoriatic lesion that’s trengthens the effect
of ROS and amplifies the production of
proinflammatory cytokines.
ROS trigger activation of MAPK/AP-1, NF-κB,
and JAK–STAT signaling pathways, which
subsequently induce iNOS, resulting in the
activation of NF-κB and AP-1, which evoke
the expression of the target genes.

ROS-mediated activation of the
JAK–STAT signaling pathway
ROS activate Jak2, Tyk2, and the MAPK
pathway, resulting in the activation of STAT.
Activated STAT dimers translocate into the
nucleus and bind to specific enhancer
elements, leading to downstream gene
expression (Zhou et al ,Free Radical Biology
& Medicine 47:891, 2009).

The exacerbation of psoriasis by
injury, infection, IFN-γ, and bacteria
lipopolysaccharide could involve
nitric oxide (NO) production.
Many antipsoriatic agents, including
methotrexate and cyclosporin, inhibit
its production.

iNOS, one of thethree isoforms of NOS, is
expressed in a wide variety of cell types
including keratinocytes.
It has been reported that iNOS is
overexpressed in psoriatic lesions
compared to uninvolved skin.
iNOS expression is mediated by the
activation of transcriptional factors such as
p38 MAPK , NF-κB , and JAK–STAT.

Manipulation of PsorasisManipulation of Psorasis

Psoriasis: New Immunologic Approaches toPsoriasis: New Immunologic Approaches to
TreatmentTreatment
TNF inhibitionTNF inhibition
– Antibodies to TNFAntibodies to TNF
– Soluble TNF receptorsSoluble TNF receptors
CostimulatoryCostimulatory
blockadeblockade
Adhesion moleculeAdhesion molecule
inhibitioninhibition
– LFA-1LFA-1
– CD2CD2
IL-2 activationIL-2 activation
blockadeblockade

Therapeutic Targets inTherapeutic Targets in
Psoriasis As a T Helper 17Psoriasis As a T Helper 17
Cell-Mediated DiseaseCell-Mediated Disease

Anti TNF approved forAnti TNF approved for
psoriasis treatmentpsoriasis treatment
JEADV 2010, 24 (Suppl. 5), 2–24JEADV 2010, 24 (Suppl. 5), 2–24

IL-12/IL-23 Inhibitors in PsoriasisIL-12/IL-23 Inhibitors in Psoriasis
Kauffman et al., J Invest Dermatol 123: 1037, 2004Kauffman et al., J Invest Dermatol 123: 1037, 2004
Krueger et al.,Krueger et al., N Engl J Med 356: 580, 2007N Engl J Med 356: 580, 2007
Torti et al., J Am Acad Dermatol,Torti et al., J Am Acad Dermatol,
10.1016/j.jaad.2007.07.01610.1016/j.jaad.2007.07.016

Reviewed in Torti et al., J Am Acad Dermatol, 2007 doi:
10.1016/j.jaad.2007.07.016
IL-12/IL-23 as Therapeutic TargetsIL-12/IL-23 as Therapeutic Targets
in Psoriasisin Psoriasis
Role of IL-12/IL-23 in Mouse ModelsRole of IL-12/IL-23 in Mouse Models
Experimental psoriasis is abolished by anti-p40 Ab therapyExperimental psoriasis is abolished by anti-p40 Ab therapy
Transgenic overexpression of p40 results in skin inflammationTransgenic overexpression of p40 results in skin inflammation
IL-23 injection results in skin inflammationIL-23 injection results in skin inflammation
Expression of IL-12/IL-23 in Human PsoriasisExpression of IL-12/IL-23 in Human Psoriasis
p40 mRNA and protein are increased in psoriatic lesionsp40 mRNA and protein are increased in psoriatic lesions
p19 mRNA and protein are increased in psoriatic lesionsp19 mRNA and protein are increased in psoriatic lesions
IL-12 and IL-23 decrease after conventional psoriatic therapyIL-12 and IL-23 decrease after conventional psoriatic therapy
A polymorphism in p40 gene is associated with susceptibility to psoriasisA polymorphism in p40 gene is associated with susceptibility to psoriasis
Clinical Studies with anti-p40 mAbClinical Studies with anti-p40 mAb

Effect of a single 5 mg/kg doseEffect of a single 5 mg/kg dose
of anti-p40 mAb in psoriasisof anti-p40 mAb in psoriasis
Kauffman et al., J Invest Dermatol 123: 1037,
2004

Current Rheumatology Reports 2007, 9:461–467

Topical Macrolactam AscomycinTopical Macrolactam Ascomycin
Analog(Analog( ABT-281ABT-281) in Psoriasis) in Psoriasis
Topical application of 3%Topical application of 3% ABT-281ABT-281 inin
acetone/olive oil showed its superioracetone/olive oil showed its superior
efficacy, its rapid systemicefficacy, its rapid systemic
clearance following uptake into the bloodclearance following uptake into the blood
stream .stream .
Its ability to inhibit cytokine biosynthesis ofIts ability to inhibit cytokine biosynthesis of
both Th1 and Th2 cell subsets, suggests thatboth Th1 and Th2 cell subsets, suggests that
it will have a broad therapeutic value init will have a broad therapeutic value in
inflammatory skin diseases, includinginflammatory skin diseases, including
psoriasis (psoriasis ( Mollison et alMollison et al Journal ofJournal of
Investigative DermatologyInvestigative Dermatology ,1999,,1999,112112, :729–, :729–
738;738;).).

A NEW CONCEPTA NEW CONCEPT
Given the side effects and limitations ofGiven the side effects and limitations of
current antipsoriatic therapies, includingcurrent antipsoriatic therapies, including
blockers TNF-_ for long term diseaseblockers TNF-_ for long term disease
control ,new strategies targeting PDCs andcontrol ,new strategies targeting PDCs and
PDC-derived IFN-_ should be consideredPDC-derived IFN-_ should be considered
both for prevention and early therapeuticboth for prevention and early therapeutic
intervention in psoriasis and, potentially,intervention in psoriasis and, potentially,
other related autoimmune diseasesother related autoimmune diseases (Nestle,
et al 2005 JEM. 202, July 4:135–143).

Future Psoriasis TherapyFuture Psoriasis Therapy
((Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–189)

Future Psoriasis TherapyFuture Psoriasis Therapy
((Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–
189)

IL-17A blocker & early promiseIL-17A blocker & early promise
for psoriasisfor psoriasis
Selective inhibition of the proinflammatory cytokineSelective inhibition of the proinflammatory cytokine
interleukin-17A using a novel fully humaninterleukin-17A using a novel fully human
monoclonal antibody (AIN457) showed considerablemonoclonal antibody (AIN457) showed considerable
early promise for treatment of psoriasis .early promise for treatment of psoriasis .
Participants were randomized to a singleParticipants were randomized to a single
intravenous infusion of AIN457 at 3 mg/kg orintravenous infusion of AIN457 at 3 mg/kg or
placebo and then followed for 12 weeks.placebo and then followed for 12 weeks.
The mean decrease in PASI score 4 weeks after theThe mean decrease in PASI score 4 weeks after the
infusion was 58% in the AIN457-treated patients andinfusion was 58% in the AIN457-treated patients and
4% with placebo4% with placebo ((BB JancinJancin
Skin & Allergy NewsSkin & Allergy News,, 20092009 ))

TARGETS inTARGETS in
PSORIASIS THERAPYPSORIASIS THERAPY

Message HomeMessage Home
STAT3STAT3 protein has emerged as an important determinant of whetherprotein has emerged as an important determinant of whether
the naïve T cell differentiates into regulatory (the naïve T cell differentiates into regulatory (Treg)Treg) or an inflammatoryor an inflammatory
((Th17)Th17) T cell lineage.T cell lineage.
STAT3STAT3 also has potent anti-inflammatory effects and regulates criticalalso has potent anti-inflammatory effects and regulates critical
cellular processes such as, cell growth, apoptosis and transcription ofcellular processes such as, cell growth, apoptosis and transcription of
inflammatory genes.inflammatory genes.
It is necessary to have both activated STAT3 in keratinocytes andIt is necessary to have both activated STAT3 in keratinocytes and
infiltrating, activated T cells to develop psoriasis. "infiltrating, activated T cells to develop psoriasis. "Neither is sufficientNeither is sufficient
alonealone
Dysregulation ofDysregulation of STAT3STAT3 pathway has therefore been implicated in thepathway has therefore been implicated in the
development of chronic inflammatory diseases, as well as, a numberdevelopment of chronic inflammatory diseases, as well as, a number
of malignant and neurodegenerative diseases.of malignant and neurodegenerative diseases.
New insights from animal models of psoriasis as an exemplar ofNew insights from animal models of psoriasis as an exemplar of
critical roles thatcritical roles that STAT3STAT3 pathways play in inflammatory diseasespathways play in inflammatory diseases
including psoriasis and on how inhibitingincluding psoriasis and on how inhibiting STAT3STAT3 can be exploited tocan be exploited to
mitigate pathogenic autoimmunity(mitigate pathogenic autoimmunity(EgwuaguEgwuagu Cytokine 47 (2009) 149–156Cytokine 47 (2009) 149–156))

Message HomeMessage Home
Stat3 is Key intracellular signaling moleculeStat3 is Key intracellular signaling molecule
important inimportant in Th17Th17 development and mediatesdevelopment and mediates IL-22IL-22––
induced keratinocyte hyperproliferation.induced keratinocyte hyperproliferation.
Stat 3 is important for differentiation of dermalStat 3 is important for differentiation of dermal
plasmacytoid dendritic cells.plasmacytoid dendritic cells.
Blocking of stat3 pathway is good-to-excellentBlocking of stat3 pathway is good-to-excellent
(similar to(similar to TNF-aTNF-a inhibitors): major signalinginhibitors): major signaling
pathway inhibition may have expected goodpathway inhibition may have expected good
clinical results in psoriasis .clinical results in psoriasis .

Stat3 &other target proteins in psoriasis by yousry a mawla

Recomendados

Recomendados

Mais conteúdo relacionado

Mais procurados

Mais procurados (20)

Destaque

Destaque (8)

Semelhante a Stat3 &other target proteins in psoriasis by yousry a mawla

Semelhante a Stat3 &other target proteins in psoriasis by yousry a mawla (20)

Mais de M.YOUSRY Abdel-Mawla

Mais de M.YOUSRY Abdel-Mawla (17)

Último

Último (20)

Stat3 &other target proteins in psoriasis by yousry a mawla