Cytokine-induced interleukin-1 receptor antagonist release in mononuclear phagocytes.
IL-1ra has recently been shown to suppress both cytokine- and endotoxin-induced IL-1 beta and TNF-alpha release from monocytes. Given that mononuclear phagocytes can produce both the proinflammatory cytokines IL-1 alpha, IL-1 beta, and TNF-alpha as well as the suppressive cytokine IL-1ra, we proposed that IL-1 alpha, IL-1 beta, and TNF-alpha may induce IL-1ra from mononuclear phagocytes. To test this hypothesis, human mononuclear cells were stimulated for 18 h with IL-1 alpha, IL-1 beta, or TNF-alpha, and the supernatants assayed for IL-1ra by ELISA. Each cytokine induced IL-1ra secretion in a dose-response manner. However, IL-1 alpha and IL-1 beta were better inducers of IL-1ra than was TNF-alpha. IL-1 alpha or IL-1 beta at a dose of 10 ng/ml induced 3 to 6 ng/ml of IL-1ra, while TNF-alpha at a dose of 100 ng/ml stimulated only 1.4 ng/ml of IL-1ra. This induction was not due to endotoxin, as all cytokines contained less than 10 pg/ml of contaminating LPS. Furthermore, for IL-1 beta-induced IL-1ra, immunoprecipitation of IL-1 beta with an anti-IL-1 beta antibody, but not a preimmune antibody, blocked the induction of IL-1ra. In contrast to mononuclear phagocytes, IL-1 alpha, IL-1 beta, and TNF-alpha did not induce further IL-1ra production in alveolar macrophages. This lack of macrophage responsiveness may relate to the constitutive production of IL-1ra by these mature mononuclear phagocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Marsh
C B
CB
Division of Pulmonary and Critical Care Medicine, Ohio State University, Columbus.
Wewers
M D
MD
D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha