title: Effect of interleukin-1 (IL-1) blockade on cytokine synthesis: II. IL-1 receptor antagonist inhibits lipopolysaccharide-induced cytokine synthesis by human monocytes.
abstract: Lipopolysaccharide (LPS) stimulates interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) gene expression and synthesis in human peripheral blood mononuclear cells (PBMC). IL-1 can also induce PBMC to synthesize IL-1 and TNF alpha. In the present study, we used IL-1 receptor antagonist (IL-1ra) to determine the relative contribution of an IL-1-positive feedback loop to the total amount of LPS-induced cytokine synthesis. Pretreatment of PBMC with human recombinant IL-1ra reduced LPS-induced cytokine synthesis in a dose-dependent manner (P less than .001). Maximal inhibition was 33% for IL-1 alpha (P less than .01), 43% for IL-1 beta (P = .001), and 20% for TNF alpha (P less than .05). We consistently observed IL-1ra suppression of LPS-induced cytokines in PBMC of 38 volunteers. However, this phenomenon was not specific for LPS; 1 microgram/mL IL-1ra inhibited IL-1 beta synthesized in response to human recombinant IL-2 by 44% (P less than .001), toxic shock syndrome toxin-1 by 26% (P less than .05), and phorbol 12-myristate 13-acetate by 76% (P less than .001). IL-1ra added to PBMC 4 or 8 hours after stimulation with LPS still inhibited IL-1 beta synthesis by 44% (P less than .001) or 25% (P = .01), respectively. The steady state messenger RNA levels of IL-1 beta were reduced in PBMC stimulated by LPS in the presence of IL-1ra. In monocytes isolated by elutriation, IL-1ra reduced LPS-induced IL-1 alpha by 16% (P less than .001), IL-1 beta by 14% (P less than .05), and TNF alpha by 24% (P = .01). We conclude that IL-1-induced IL-1 significantly contributes to LPS-induced cytokine synthesis.
authors.affiliation: Department of Medicine, New England Medical Center Hospitals, Boston, MA.
authors.forename: E V
authors.initials: EV
authors.lastname: Granowitz
authors.forename: E
authors.initials: E
authors.lastname: Vannier
authors.forename: D D
authors.initials: DD
authors.lastname: Poutsiaka
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides; D009000:Monocytes / Q000378:metabolism*; D011506:Proteins / Q000494:pharmacology*; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011506:Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha