Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease

Abstract

Interleukin-1 receptor antagonist (IL-1ra) is a 22-Kd protein that shares homology with IL-1 beta, binds to the IL-1 receptor, but has no known agonist properties. This inhibitor appears to be the first cytokine whose sole function is to block the actions of another cytokine. Exogenous IL-1ra administration has been shown to reduce mortality in experimental septic shock. We now report that IL-1ra is endogenously produced and circulates in experimental inflammation and in clinical disease. After experimental endotoxemia in human volunteers, IL-1ra concentrations increase from a baseline concentration of 460 +/- 200 pg mL-1 to 14,870 +/- 290 pg mL-1 at 3 hours (P less than .05). IL-1ra is also detectable in all plasma samples from critically ill patients with a mean concentration of 8,680 +/- 2,060 pg mL-1 (range 320 to 55,370 pgs mL-1). In nonhuman primates, Escherichia coli septic shock induces elevated plasma levels of IL-4ra (P less than .05). However, in animals that eventually succumb to septic shock, Il-1ra appears in quantities presumed inadequate to block the pathologic sequelae associated with high IL-1 beta levels. The findings suggest that IL-1ra may play a role in modulating the systemic host responses to a variety of nonlethal disease states by altering the balance between cytokines and their antagonists.

Interleukin‐1 receptor antagonist levels correlate with extent of myocardial loss in patients with acute myocardial infarction

“…8,9 Interleukin-1Ra is a competitive inhibitor of the IL-1 membrane receptor without agonistic effects and is locally released by activated cells (i.e., monocytes) or produced by hepatocytes as acute phase reactant; 8,9 IL-1Ra secretion occurs simultaneously with activation of IL-1 receptor to modulate proinflammatory effects of IL-1, and IL-1Ra values correlate well with grade of inflammation. [8][9][10] Elevation of IL-1Ra occurs early in patients with acute MI, often preceding the rise of markers for necrosis. 6 In a previous study of patients with acute MI, 7 elevated IL-1Ra peak levels during coronary care unit stay were associated with hemodynamic impairment, but did not correlate with peak CK values.…”

Anti-inflammatory properties of human serum IgA: induction of IL-1 receptor antagonist and FcαR (CD89)-mediated down-regulation of tumour necrosis factor-alpha (TNF-α) and IL-6 in human monocytes

“…LPS) or FcR cross-linking by IgGcontaining immune complexes [22,23,29,30]. However, the regulatory potential of cytokine inhibitors produced in response to proinflammatory stimuli could be insufficient in an overwhelming acute or chronic inflammatory response associated with the release of high levels of proinflammatory cytokines [45][46][47]. By controlling the activity of proinflammatory cytokines at two distinct levels, i.e.…”

Circulating proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and IL-1 receptor antagonist (IL-1Ra) in fulminant hepatic failure and acute hepatitis

“…In a large number of patients with chronic liver diseases, increased circulating levels of IL-lRa have been reported and shown to be related to disease activity [34]. High IL-iRa levels have also been reported in patients with experimental endotoxaemia [35] and high-dose exogenous IL-lRa has been highly effective in reducing the lethality of endotoxin-induced shock in animals [36,37]. This supports the contention that endogenous IL-1 Ra may not be adequate to significantly neutralize the effects of endogenous IL-l in individuals that succumb to septic shock [38].…”