Atherosclerosis and inflammation. Patterns of cytokine regulation in patients with peripheral arterial disease

Inflammatory phenomena at sites of atherosclerotic plaques are increasingly thought to be major determinants of the progression and clinical outcome o f atherosclerotic disease. Therefore, attention is being paid to systemic m arkers/mediators which may reflect the inflammatory activity in the plaques . This study evaluates the pattern of the main proinflammatory cytokines tu mor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6), their soluble receptors/antagonist, and a variety of inflammatory markers, in patients with peripheral arterial disease (PAD). E ight patients with PAD suffering from claudicatio intermittens (CI), eight with critical limb ischemia (CLI) and eight controls (C) were studied. Bloo d samples were collected at baseline in all groups and, for C and CI, immed iately after and 4 h after a 30-min treadmill test. Baseline: no difference s in cytokine plasma levels were detected among the three groups. In contra st, soluble receptors of TNF (type I and II) and of IL-6, and IL-1 beta rec eptor antagonist (IL-1ra) were increased in CI and CLI patients, as compare d to C. Of note, IL-1ra correlated with the occurrence and stage of the dis ease in a highly significant proportion of the patients, reaching a predict ive value for the disease of P < 0.0001. The opposite trend was observed fo r the soluble receptor of IL-1 beta. Notably, in the patients no alteration s could be found in white blood cell counts, expression of CD11c adherence molecule by circulating monocytes or, in vitro, O-2(-) release from zymosan -activated neutrophils. Moreover, plasma levels of platelet activating fact or (PAF), of neutrophil elastase and of the acute phase reactants C-reactiv e protein (CRP) and alpha 1-acid glycoprotein were not found to be signific antly altered. In contrast, the acute-phase proteins ctl-antitrypsin (alpha 1AT) and haptoglobin (HG) were found to be increased. Effect of treadmill: IL-IP and TNFa remained at baseline levels following exercise, and IL-6 dr opped to undetectable levels. Among cytokine antagonists, again the most re levant changes concerned the IL-1ra, which was significantly increased imme diately after the treadmill test, both in CI and C, and returned to baselin e levels after 4 h. In contrast, soluble TNF alpha, IL-1 beta and IL-6 rece ptors, PAF, and the other markers of leukocyte activation were not found to be altered. Soluble TNF alpha and IL-6 receptors were shown to inhibit the biological effects of their ligands. Similarly, IL-1ra and the acute phase proteins alpha 1AT and HG have been reported to exert anti-inflammatory fu nctions. The increased plasma levels of these agents, together with low lev els of inflammatory cytokines and other pro-inflammatory mediators such as PAF and al-acid glycoprotein, appear to draw an undescribed picture, so far , of upregulation of a composite systemic anti-inflammatory mechanism in at herosclerotic patients. IL-1ra appears to be a reliable marker of the state of activation of this mechanism. These results may provide a basis for dev eloping new insights into the pathogenesis of the atherosclerotic disease. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.