IL-1ra suppresses endotoxin-induced IL-1 beta and TNF-alpha release from mononuclear phagocytes.
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)
Marsh
C B
CB
Division of Pulmonary and Critical Care Medicine, Ohio State University, Columbus 43210.
Moore
S A
SA
Pope
H A
HA
Wewers
M D
MD
D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D016676:Macrophages, Alveolar / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D010586:Phagocytes / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D004731:Endotoxins; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha