title: Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55.
abstract: The aim of this study was to investigate whether interleukin (IL)-6 induces the production of IL-1 and tumor necrosis factor (TNF) antagonists. Serial plasma samples were obtained from cancer patients participating in phase I and II trials of recombinant IL-6 administered as a 120-hour continuous intravenous (IV) infusion. Plasma IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor p55 (TNFsRp55) levels were measured by specific radioimmunoassays (RIAs). IL-1Ra levels increased rapidly, reaching peak values (9.6 +/- 1.7 ng/mL) within 2 to 4 hours of beginning treatment. Thereafter, levels promptly declined, reaching near baseline within 24 hours despite continuation of IL-6. TNFsRp55 plasma levels increased within 4 to 8 hours after initiating treatment and increased progressively throughout the duration of therapy. IL-1 beta and TNF-alpha plasma levels were below the detection limit in all samples tested. Peripheral blood mononuclear cells (PBMC) exposed to IL-6 produced only small amounts (1.56 +/- 0.3 ng/mL) of IL-1Ra, even in the presence of exogenous soluble IL-6 receptor (gp80). TNFsRp55 levels measured in the supernatants of IL-6-stimulated PBMC were below the detection limit of the assay. Macrophages generated by culturing monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) were much more responsive to IL-6 than freshly isolated unfractionated or adherent PBMC and synthesized almost as much IL-1Ra when stimulated with IL-6 as with endotoxin. These results suggest that the antinflammatory properties of IL-6 may be due; in part, to the induction of IL-1Ra synthesis and the release of soluble TNF receptors. Our findings also suggest that tissue macrophages may be an important source of IL-6-induced IL-1Ra.
authors.affiliation: Department of Medicine, New England Medical Center, Boston, MA 02111.
authors.forename: H
authors.initials: H
authors.lastname: Tilg
authors.forename: E
authors.initials: E
authors.lastname: Trehu
authors.forename: M B
authors.initials: MB
authors.lastname: Atkins
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: J W
authors.initials: JW
authors.lastname: Mier
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D009369:Neoplasms / Q000097:blood / Q000628:therapy; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor