IL-1ra suppresses endotoxin-induced IL-1 beta and TNF-alpha release from mononuclear phagocytes

Abstract

The proinflammatory effects of lipopolysaccharide (LPS) are modulated in large part through the induction of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) release by mononuclear phagocytes. However, IL-1's target cell effects can be suppressed by IL-1 receptor agonist (IL-1ra). Because mononuclear phagocytes produce and respond to IL-1 via IL-1 receptors, we hypothesized that IL-1ra may also be able to block receptors on IL-1 producer cells and inhibit secondary IL-1-induced IL-1 production. To test this hypothesis, mononuclear cells and alveolar macrophages were stimulated with LPS in the presence of IL-1ra and analyzed for IL-1 beta and TNF-alpha production. For mononuclear cells, IL-1ra inhibited 6-h LPS- and IL-1 alpha-induced IL-1 beta release to 66 +/- 4% (P = 0.001 by paired t test) and 39 +/- 7% (P = 0.0005 by paired t test) of control, respectively. In addition, IL-1ra reduced both LPS- and IL-1 alpha-stimulated IL-1 beta mRNA levels to 78 and 37% of control, respectively. Furthermore, IL-1ra downregulated both LPS and IL-1 alpha-induced TNF-alpha release to 84 +/- 4% (P = 0.012 by paired t test) and 49 +/- 9% (P = 0.001 by paired t test) of control, respectively. Alveolar macrophages demonstrated variable IL-1ra-induced suppression of LPS-stimulated IL-1 beta and TNF-alpha release.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-inflammatory response is associated with mortality and severity of infection in sepsis

“…3A). The exact mechanism of TNF-␣ suppression is unclear; however, a previous study has shown that IL-1ra suppresses TNF-␣ release from macrophages (22). At 6 h following CLP, IL-1␤ and TNF-␣ levels in liver homogenates were not significantly different from baseline.…”

Proinflammatory Cytokines Are Not Released in the Circulation Following Acute Pulmonary Thromboembolism in Pigs

“…TNF-® is known to be released into the systemic circulation within the rst few hours after the infusion of bacteria or lipopolysacharide into an experimental animal [16]. IL-1¯, which is also released early after sepsis, interacts closely and acts synergistically with TNF-® [19]. IL-8 is released a few hours later and has signi cant chemotatic effects on the leukocytes in the pulmonary circulation [20,24].…”

“…We propose that early proin ammatory cytokines [16], such as TNF-®, IL-1¯, and IL-8, may be also be involved in the early phase of APTE. TNF-® is a cytotoxic and proin ammatory cytokine that mediates apoptosis, cell proliferation, and immunomodulation in many pathological conditions [17,18], while IL-1¯acts similarly and causes increase in the vascular permeability of the lung following a wide variety of injuries [19]. The CXC chemokine interleukin-8 (IL-8) is an important activator and chemoattractant for neutrophils and has been implicated in many in ammatory diseases [20][21][22].…”

Administration of neutralizing antibody against rabbit IL-1 receptor antagonist exacerbates lipopolysaccharide-induced arthritis in rabbits

“…Thus, there is evidence that the production of IL-1/3 at 2 h was mainly mediated by TNF(~. In contrast, neutralization of endogenous IL-lra had no effects on TNFc~ activity, which means that the production of TNFo~ is not mediated by IL-1 in LPSarthritis, although IL-1 does induce TNF~ in vitro [39,40].…”