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Hepatocyte Growth Factor Significantly Suppresses Collagen-Induced Arthritis in Mice

Katsuhide Okunishi^*, Makoto Dohi^1,*, Keishi Fujio^*, Kazuyuki Nakagome^*, Yasuhiko Tabata, Takahiro Okasora, Makoto Seki, Mihoko Shibuya^*, Mitsuru Imamura^*, Hiroaki Harada^*, Ryoichi Tanaka^* and Kazuhiko Yamamoto^*

^* Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Institute of Frontier Medical Sciences, Kyoto University, Kyoto, Japan; and Research Laboratory III, Pharmaceutical Research Division, Mitsubishi Pharma Corporation, Yokohama, Japan

Hepatocyte growth factor (HGF) plays an important role in angiogenesis, cell proliferation, antifibrosis, and antiapoptosis. Moreover, recent studies have highlighted the immunosuppressive effect of HGF in animal models of allogenic heart transplantation and autoimmune myocarditis and in studies in vitro as well. We also reported that HGF significantly suppresses dendritic cell function, thus down-regulating Ag-induced Th1-type and Th2-type immune responses in allergic airway inflammation. However, the immunosuppressive effect of HGF in many other situations has not been fully clarified. In the present study, using a mouse model of collagen-induced arthritis (CIA) and experiments in vitro, we examined the effect of HGF on autoimmune arthritis and then elucidated the mechanisms of action of HGF. To achieve sufficient delivery of HGF, we used biodegradable gelatin hydrogels as a carrier. HGF suppressed Ag-induced T cell priming by regulating the functions of dendritic cells in the Ag-sensitization phase with down-regulation of IL-10. In contrast, under continuous Ag stimulation HGF induced IL-10-producing immunocytes both in vivo and in vitro. Moreover, HGF potently inhibited the development of CIA with enhancing the Th2-type immune response. We also confirmed that HGF significantly suppressed the production of IL-17 by immunocytes. These results indicate that HGF suppresses the development of CIA through different ways at different phases. They also suggest that HGF could be an attractive tool for treating patients with rheumatoid arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Makoto Dohi, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. E-mail address: mdohi-tky{at}umin.ac.jp

² Abbreviations used in this paper: HGF, hepatocyte growth factor; CIA, collagen-induced arthritis; CII, type II collagen; DC, dendritic cell; EU, ELISA unit; LN, lymph node; RA, rheumatoid arthritis; rhHGF, recombinant human HGF; Treg, regulatory T.