Interleukin (IL)-6 and Its Soluble Receptor Induce TIMP-1 Expression in Synoviocytes and Chondrocytes, and Block IL-1-induced Collagenolytic Activity

• Published in: The Journal of biological chemistry 1998-05, Vol.273 (22), p.13625-13629
• Main Authors: Silacci, Paolo, Dayer, Jean-Michel, Desgeorges, Alain, Peter, Robin, Manueddu, Claude, Guerne, Pierre-André
• Format: Article
• Language: English
• Subjects: Cartilage, Articular - cytology; Cartilage, Articular - metabolism; Cells, Cultured; Fibroblasts - metabolism; Gene Expression Regulation - physiology; Humans; Interleukin-6 - physiology; Kinetics; Receptors, Interleukin-6 - physiology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Synovial Membrane - cytology; Synovial Membrane - metabolism; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.22.13625

To define the potential role of interleukin-6 (IL-6) and its soluble receptor α in cartilage metabolism, we analyzed their effects on tissue inhibitor of metalloproteases (TIMP) synthesis by synoviocytes and chondrocytes. TIMP-1 production by isolated human articular synovial fibroblasts and chondrocytes, stimulated by IL-6 and/or its soluble receptor, was first assayed by specific enzyme-linked immunosorbent assay; the slight stimulatory effect of IL-6 on TIMP-1 production by both types of cells was markedly amplified by the addition of soluble receptor, the maximal secretion being observed only at 96 h. TIMP-1 mRNA expression, determined by ribonuclease protection assay, was induced by IL-6 together with its soluble receptor, but TIMP-2 and -3 mRNAs were not affected by these factors. A specific neutralizing antibody abolished the effects of the soluble receptor. Finally, supernatant from synoviocytes stimulated by IL-6 plus its soluble receptor blocked almost completely the collagenolytic activity of supernatant from IL-1-induced synoviocytes. These observations indicate that IL-6 and its soluble receptor have a protective role in the metabolism of cartilage. Given the high levels of soluble receptor in synovial fluid and the marked induction of IL-6 by IL-1 or TNF-α, it is likely that IL-6 and its soluble receptor are critical in controlling the catabolic effects of pro-inflammatory cytokines.