Editorial Slides VP Watch –June 12, 2002 - Volume 2, Issue 23

CRP, IL-6, CD-40, PAPP-a, CTX-3, IL-18,…Which One?

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.

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.

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

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

IL-18/IL-18BP in AtherosclerosisIL-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

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

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

HRR Lower CI Upper CI P valueAge, 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 CADStefan 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

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.

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?

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?

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