International Immunology Advance Access originally published online on July 5, 2004
International Immunology 2004 16(8):1099-1108; doi:10.1093/intimm/dxh111
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© 2004 The Japanese Society for Immunology
ORIGINAL RESEARCH PAPERS |
Involvement of IL-17 in Fas ligand-induced inflammation
1 Center for the Development of Molecular Target Drugs, Cancer Research Institute and 2 Department of Transgenic Animal Science, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan
3 Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo 108-8639, Japan
4 Center of Molecular Biosciences, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
Correspondence to: T. Suda; E-mail: sudat{at}kenroku.kanazawa-u.ac.jp
Fas ligand (FasL) has been well characterized as a death factor. However, recent studies revealed that ectopic expression of FasL induces inflammation associated with massive neutrophil infiltration. We previously demonstrated that the neutrophil infiltration-inducing activity of FasL is partly dependent on, but partly independent of, IL-1ß. Here we investigated the cytokine profile of peritoneal lavage fluid obtained from mice that received i.p. injections of FFL, a FasL-expressing tumor cell line. We found that FFL injection caused a marked increase of not only IL-1ß but also IL-6, IL-17, IL-18, KC/chemokine CXC ligand 1 and macrophage inflammatory protein (MIP)-2, but not of IL-1
, IFN-
, TGF-ß or TNF-. The FFL-induced cytokine production was not observed in Fas-deficient lpr mice. Among cells transfected to express individually IL-1ß, IL-6, IL-17, or IL-18, only those expressing IL-1ß and IL-17 induced neutrophil infiltration. In these analyses, as little as 20 pg of peritoneal IL-17 induced neutrophil infiltration. The peritoneal IL-17 levels after FFL-injection were greatly diminished in IL-1-deficient mice. However, the IL-17 level was still above the threshold for neutrophil infiltration. Consistent with this, co-administration of the anti-IL-17 antibody with FFL diminished the peritoneal KC levels and neutrophil infiltration in IL-1-deficient mice. In addition, the expression of IL-17 by the tumor cells inhibited tumor growth in wild-type and nude mice. These results indicate that FasL is an upstream inflammatory factor that induces a variety of other inflammatory cytokines in vivo, and suggest that IL-17 is involved in FasL-induced inflammation in the absence of IL-1ß.
Keywords: cytokines, inflammation, rodent, T lymphocytes, tumor immunity
M. Umemura and T. Kawabe contributed equally to this work
Transmitting editor: N. Shigekazu
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