1) The document discusses interleukin-18 (IL-18), an inflammatory cytokine that plays a role in atherosclerosis and plaque instability. Studies have shown IL-18 is overexpressed in atherosclerotic plaques and higher levels predict future cardiovascular events. 2) One study found serum IL-18 levels were significantly higher in coronary artery disease patients who suffered fatal cardiovascular events compared to those who did not. High IL-18 levels were an independent predictor of death even after adjusting for other risk factors. 3) IL-18 is thought to promote plaque inflammation and vulnerability through stimulating interferon-gamma production, and blocking this pathway in mice prevents the effects of IL-18 on atherosclerosis. However, questions remain around

1. Editorial Slides
VP Watch –June 12, 2002 - Volume 2, Issue 23
CRP, IL-6, CD-40, PAPP-a, CTX-3, IL-18,…
Which One?

2.  Atherosclerosis is an inflammatory disease. 1
 Inflammatory processes play a pivotal role in
the pathogenesis of atherosclerosis and
mediate many of the stages of atheroma
development from leukocyte recruitment to
eventual rupture of the vulnerable plaque. 1
 Elevated levels of P-selectin, ICAM-1, IL-6,
TNF-α , and CRP have been shown to predict
future vascular risk in a variety of clinical
settings.

3.  A previously unknown inducer of interferon-
gamma (IFN-γ) was discovered and named
interleukin-18 (IL-18) in 1989.
 IL-18 stimulates IFN-γ production by initiating IFN-
γ gene transcription via activation of the IFN-γ
promoter.
 Cells known to express IL-18 include
macrophages, keratinocytes, glucocorticoid-
secreting adrenal cortex cells, and osteoblasts.

4.  Studies showed that IL-18 induces IFN-γ expression not
only in macrophages, but also in vascular SMCs.
 Both IL-18 and IL-18R (receptor) /ß are over -expressed
within human atheroma in situ compared with non-diseased
arterial tissue.4
 Whitman and colleagues showed that exogenous IL-18
increases atherosclerotic plaque development in ApoE
deficient mice through enhancement of an inflammatory
response via an IFN-γ dependent mechanism.6
 Mallat et al. found that exogenous expression of the murine
IL-18 binding protein (the endogenous inhibitor of IL-18)
reduced plaque development in ApoE-KO mice. 7

5.  Mallat and colleagues also showed that IL-
18 levels are related to pathological and
clinical signs of plaque instability.3
 Their results suggest an important role for
IL-18 in ischemic myocardial dysfunction
leading to severe clinical events and
eventually to death.3

6. 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
Ulceration No Ulceration
mRNA expression
(relative to GAPDH)
1
0
2
3
4
Mallat Z, Corbaz A, Scoazec A, Besnard S, Lesèche G, Chvatchko Y, Tedgui A. Expression of interleukin-18 in human
atherosclerotic plaques and relation to plaque instability. Circulation. . 2001; 104: 1598–1603.
Quantitative data for IL-18 mRNA expression according to
clinical (A) or pathological (B) signs of plaque instability
were displayed graphically.
A B

7.  As reported in VP Watch of this
week, Blankenberg and colleagues showed
that median serum concentration of IL-18
was significantly higher among CAD patients
who had a fatal cardiovascular event than
among those who did not have fatal events.8

8.  They showed that the hazard risk ratio of
future cardiovascular death increased with
increasing quartiles of IL-18. 8
 After adjustment for most potential
confounders, including ejection fraction as
well as IL-6, hsCRP, and fibrinogen, this
relation remained almost unchanged, such
that patients within the highest quartile of IL-
18 had a 3.3-fold increase in hazard risk
compared with those in the first quartile.8

9. HRR Lower CI Upper CI P value
Age, Y 1.05 1.02 1.09 0.002
Diabetes 1.77 1.00 3012 0.05
Hypertention 1.10 0.64 2.18 0.6
HDL 1.01 0.78 1.31 0.9
Trigelyceride 1.9 0.85 1.40 0.5
Number of vessel disease 0.53 0.66 1.24 0.5
Β-Blocker 0.74 0.44 1.25 0.3
Statin therapy 0.73 0.39 1.36 0.3
Ejection fraction 0.97 0.96 0.98 <0.0001
hs-CRP 0.94 0.70 1.25 0.7
Fibrinogen 1.19 0.88 1.50 0.2
IL-6 1.15 0.90 1.49 0.3
IL-18 1.50 1.17 1.92 0.001
Independent predictors of death from cardiovascular causes after a median
follow-up of 3.9 years in cox regression model when all variables presented
simultaneously in 1229 patients with CAD
Stefan Blankenberg, Laurence Tiret, Christoph Bickel, Dirk Peetz, François Cambien, Jürgen Meyer, and Hans J. Rupprecht; Interleukin-18 Is a
Strong Predictor of Cardiovascular Death in Stable and Unstable Angina; Circulation published June 3, 2002
HRR=Hazard Risk Ratios

10. Conclusion
• Expression of IL-18 is associated with the
presence of both clinical (unstable symptomatic
plaque) and pathological (ulcerated plaque)
signs of plaque vulnerability.
• Serum IL-18 is a strong independent predictor of
death from cardiovascular causes in patients
with coronary artery disease regardless of the
clinical status at admission.

11. Questions:
• Surprisingly in this study a number of well
known predictors of outcome such as lipid-
lowering therapy did not correlate with the
outcome. How representative is the study
population?
• Is IL-18 an independent predictor of future
coronary events in healthy population as
well as symptomatic patients?

12. Questions:
• Is the effect of IL-18 on plaque inflammation /
vulnerability mediated only by INF-γ? If so, does
blocking INF-γ (INF-KO mice) prevent the effect
of IL-18 on atherosclerotic plaque?
• Since IL-18 is a non-specific proinflammatory
cytokine, does serum IL-18 increase in response
to common infections? If so would that be
significant enough to affect the plaque stability?

13. 1) Ross, R. 1999. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 340:115–126.
2) Dinarello CA. Interleukin-18: a proinflammatory cytokine. Eur Cytokine Netw. . 2000; 11: 483–486.
3) Mallat Z, Corbaz A, Scoazec A, Besnard S, Lesèche G, Chvatchko Y, Tedgui A. Expression of interleukin-18 in human atherosclerotic
plaques and relation to plaque instability. Circulation. . 2001; 104: 1598–1603.
4) Gerdes N, Sukhova GK, Libby P, Reynolds RS, Young JL, Schonbeck U.; Expression of interleukin (IL)-18 and functional IL-18 receptor
on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis.; J Exp Med. 2002 Jan
21;195(2):245-57.
5) Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001; 89: 763–771.
6) Whitman SC, Ravisankar P, Daugherty A.; Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of
interferon-gamma.; Circ Res 2002 Feb 8;90(2):E34-8
7) Mallat Z, Corbaz A, Scoazec A, Graber P, Alouani S, Esposito B, Humbert Y, Chvatchko Y, Tedgui A. Interleukin-18/interleukin-18
binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res. 2001; 89: e41–e45.
8) Stefan Blankenberg, Laurence Tiret, Christoph Bickel, Dirk Peetz, François Cambien, Jürgen Meyer, and Hans J. Rupprecht;
Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina; Circulation published June 3, 2002
References