Increased circulating Interleukin-18 levels in centenarians with no signs of vascular disease: another paradox of longevity?

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Abstract

Interleukin (IL)-18 is highly expressed in macrophages from human atherosclerotic plaques, suggesting its involvement in ischemic syndromes. We evaluated IL-18 and IL-18 binding protein (BP) in healthy centenarians, as longevity is characterized by a reduced incidence of ischemic events. For comparison, patients with chronic ischemic syndromes (CIS) were evaluated. Serum IL-18 and IL-18BP levels were measured by non-cross-reacting ELISA in 16 healthy centenarians and in two age-control populations, each of 18 healthy individuals aged 55.9±1.43 and 74.3±1.35, respectively, as well as in 23 CIS patients, and another cohort of 23 healthy subjects that were age- and sex-matched with CIS patients. Centenarians displayed significantly higher total IL-18 serum levels compared to each control group. Elevated IL-18 levels were also present in CIS patients. However, centenarians had a significant higher level of IL-18BP compared to the cohort of 23 controls (P=0.0014), and compared to CIS patients (P=0.043); as a result centenarians exhibited a lower level of free IL-18 than CIS patients. The present results indicate that quenching of IL-18 by IL-18BP may explain the apparent paradox of elevated serum IL-18 with no vascular signs in centenarians.

Introduction

The reduced incidence of cardiovascular-thrombotic events in centenarians has stimulated research aimed at detecting protective mechanisms from atherosclerosis. Results from these studies are in part controversial. In fact, centenarians have high levels of the natural anti-oxidants vitamins A and E (Mecocci et al., 2000) that may be protective from atherosclerosis. But, they present enhanced coagulation enzyme activity, elevated plasma fibrinogen and homocysteine levels, which represent thrombotic risk factors for middle-aged individuals (Mari et al., 1995, Mutus et al., 2000). Thus, studies on centenarians may provide indication on the relative incidence of protective and risk factors on vascular events.

The immune-inflammatory response is of pivotal relevance in the pathogenesis of atherosclerosis (Libby et al., 2002). A network of inflammatory mediators, including arachidonic acid metabolites, cytokines, chemokines, regulate interactions between vascular and circulating cells that may facilitate the development of atheromasic lesions and determine their clinical outcome (Datta et al., 1995, Buffon et al., 2002). Moreover, gram-negative bacteria infections may be linked to atherosclerosis, as an increased resistance to atherosclerosis was found in subjects with the Asp299Gly polymorphism of the toll-like receptor 4 (TLR-4), the transmembrane receptor that signals the release of inflammatory mediators in response to gram-negative bacteria (Kiechl et al., 2002).

IL-18 is a pro-inflammatory cytokine (Dinarello, 2000), and appears to be involved in atherosclerosis. Elevated expression of IL-18 and its receptor chains (IL-18Rα/β) have been detected in atheroma (Mallat et al., 2001a, Mallat et al., 2001b, Gerdes et al., 2002). Moreover, IL-18Rα/β signals the induction of inflammatory mediators such as IL-6, IL-8, intracellular adhesion molecule (ICAM)-1, in vascular cells (Gerdes et al., 2002). IL-18 also enhances atherosclerosis in apolipoprotein E-deficient mice (Whitman et al., 2002). It has been proposed that IL-18 may play a major role in plaque destabilization and acute ischemic syndromes.

IL-18 binding protein (BP) is a constitutively expressed and secreted protein which binds IL-18 with high affinity and neutralizes its activities (Novick et al., 1999). IL-18BP protects atrial myocardium from ischemia/reperfusion-related lesions (Pomerantz et al., 2001) and prevents the onset and progression of atherosclerotic lesions in apoE knockout mice (Mallat et al., 2001a, Mallat et al., 2001b). In healthy humans, IL-18BP circulates at a 20-fold molar excess over that of IL-18, although approximately 85% of IL-18 is in the free-form (Novick et al., 2001). Thus, the simultaneous determination of serum IL-18 and IL-18BP provides an index of the bioavailability of circulating IL-18.

In this report we show that healthy centenarians have increased circulating levels of IL-18, but also present elevated IL-18BP levels that antagonize the potential deleterious effect of IL-18 on the vasculature.

Section snippets

Subjects

16 healthy centenarians (4 males and 12 females), non-smokers, without past or present history of ischemic disease, diabetes, hypertension, or nephropathy were selected. Two age-control populations each of 18 healthy individuals, (6 males, 12 females, aged 55.9±1.43 and 5 males, 13 females, aged 74.3±1.35) each in apparent good health, were also recruited. In parallel, a group of 23 patients (15 males, 8 females, aged 63.7±1.3) with CIS (8 stable angina, 11 previous myocardial infarction, 2

Results

IL-18 is highly expressed in atherosclerotic lesions, suggesting the involvement of this cytokine in the evolution of atherosclerotic plaques (Mallat et al., 2001a, Mallat et al., 2001b, Gerdes et al., 2002). To determine the relationship between circulating IL-18 levels and symptomatic atherosclerosis, we measured circulating IL-18 levels in healthy centenarians, which are characterized by a reduced incidence of vascular events, as well as in patients with CIS.

Centenarians displayed

Discussion

The present results establish that patients with chronic atherosclerosis-related ischemic syndromes display a significant increase in serum IL-18. Although circulating IL-18 levels may be influenced by several factors, this finding is consistent with the observation of high IL-18 expression in macrophages within atherosclerotic lesions (Mallat et al., 2001a, Mallat et al., 2001b, Gerdes et al., 2002). In CIS patients, serum IL-18 may increase as part of the ongoing inflammatory reaction that

Acknowledgements

This work was in part supported by grants from the University of Chieti (ex 60%) to M.R. and G.D. and from University of Messina (ex 60%) to R.A.M.

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