title: IL-6 and IL-1 synergistically enhanced the production of MMPs from synovial cells by up-regulating IL-6 production and IL-1 receptor I expression.
abstract: In the present study, we investigated potential synergism between IL-6 and IL-1 for the production of matrix metalloproteinases (MMPs) by the synovial cell line SW982. Cells were cultured with different combinations of IL-6, soluble IL-6 receptor (sIL-6R) and IL-1beta for 24h and production of MMPs was then measured. IL-6+sIL-6R, but not IL-6 alone, induced MMP-13 and MMP-3 production. IL-1beta also induced production of MMPs. Of interest, addition of IL-6+sIL-6R together with IL-1beta synergistically increased MMP production. Next, we analyzed the mechanism responsible for the synergistic effects of IL-6+sIL-6R and IL-1beta in combination. IL-1beta-induced MMP production was significantly augmented in the presence of sIL-6R. IL-1beta as well as IL-6+sIL-6R induced IL-6 production. Moreover, IL-6+sIL-6R significantly augmented expression of IL-1RI, but not IL-1RII, in SW982 cells. Responsiveness to IL-1beta was much higher in IL-6+sIL-6R-pretreated cells than non-treated cells in terms of MMP production. Finally, IL-6+sIL-6R-induced IL-1RI expression was inhibited by a STAT pathway inhibitor, but not a MAPK pathway inhibitor. These results suggest that increased expression of IL-1RI stimulated by IL-6+sIL-6R and the increased production of IL-6 on exposure to IL-1beta and IL-6+sIL-6R are involved in the observed synergistic effect on the production of MMPs by SW982 cells.
authors.affiliation: Product Research Department, Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Suzuki
authors.forename: Misato
authors.initials: M
authors.lastname: Hashizume
authors.forename: Hiroto
authors.initials: H
authors.lastname: Yoshida
authors.forename: Masashi
authors.initials: M
authors.lastname: Shiina
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
mesh_terms: D002478:Cells, Cultured; D004357:Drug Synergism; D007375:Interleukin-1 / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction; D013582:Synovial Fluid / Q000166:cytology; D015854:Up-Regulation
chemical_list: D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D019947:Receptors, Interleukin-6; D050791:STAT Transcription Factors; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3