The document discusses the role of interleukin-18 (IL-18) and its binding protein (IL-18BP) in atherosclerosis. It finds that higher levels of IL-18 are associated with more unstable atherosclerotic plaques and acute coronary events. Experiments inhibiting IL-18 signaling through overexpression of IL-18BP in mice prevented atherosclerosis and produced more stable plaques with reduced macrophages, increased smooth muscle cells and collagen. The conclusion is that IL-18/IL-18BP regulation critically impacts atherosclerosis and inhibiting IL-18 may help reduce plaque progression and promote stability.

1. Caspase-1
p10
10 Kd
hIL18R
105 Kd
75 Kd
IL-18/IL-18BP in Atherosclerosis
IL-18 and IL-18R in Human Carotid Plaques
hIL18
25 Kd
15 Kd
Atherosclerotic plaques Controls

2. IL-18/IL-18BP in Atherosclerosis
IL-18mRNA and Plaque Stability
mRNA expression
(relative to GAPDH)
** p < 0.0074
Symptomatic Asymptomatic
1
0
2
3
4
* p < 0.018
Ulcer No Ulcer
mRNA expression
(relative to GAPDH)
1
0
2
3
4

3. Plasma IL-18 in Acute Coronary Syndromes
Conclusions
• IL-18 levels are related to clinical signs of
plaque instability
• The results suggest an important role for IL-
18 in ischemic myocardial dysfunction leading
to severe clinical events and eventually to
death

4. Inhibition of IL-18 Signaling by IL-18 Binding
Protein Transfection Prevents Development
of Atherosclerosis and Induces a Stable
Plaque Phenotype in apoE KO Mice
Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S,
Esposito B, Humbert Y, Chvatchko Y, Tedgui A
INSERM U 541, IFR Circulation Paris VII, Paris , France
and Ares Serono, Geneva, Switzerland

5. 0
2
4
6
Empty plasmid IL-18BP plasmid
Lipid staining Area (%)
****
P < 0.0001
Empty
IL18BP
Role in Early Lesion Formation
in ApoE KO Mice
Lipid Staining
IL18/IL18BP Signaling in Atherosclerosis

6. Role in Advanced Lesion Composition
Empty
IL18BP
MOMA-2
0
10
20
30
40
50
60
****
P < 0.0001
Macrophage
Area(%)
0
100
200
300
***
P < 0.005Tcells/mm2
IL18/IL18BP Signaling in Atherosclerosis

7. Role in Advanced Lesion Composition
Empty Plasmid IL18BP Plasmid
α-Actin
0
4
8
12
16
20
*
P < 0.05
Smoothmuscle
CellArea(%)
IL18/IL18BP Signaling in Atherosclerosis

8. Role in Advanced Lesion Composition
Empty Plasmid IL18BP Plasmid
Sirius Red
0
10
20
30
40
50
60
***
P < 0.0005
Collagencontent(%)
IL18/IL18BP Signaling in Atherosclerosis

9. IL18/IL18BP Signaling in Atherosclerosis
Conclusion
Our results identify for the first time a critical role for
IL-18/IL-18BP regulation in atherosclerosis and
suggest a potential role for IL-18 inhibitors in
reduction of plaque development/progression and
promotion of plaque stability.

10. IL18/IL18BP Signaling in Atherosclerosis
Conclusion
Our results identify for the first time a critical role for
IL-18/IL-18BP regulation in atherosclerosis and
suggest a potential role for IL-18 inhibitors in
reduction of plaque development/progression and
promotion of plaque stability.