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International Immunology Advance Access published online on July 5, 2004
International Immunology, doi:10.1093/intimm/dxh111
© 2004 by The Japanese Society for Immunology
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Received November 19, 2003
Accepted May 10, 2004

Article

Involvement of IL-17 in Fas ligand-induced inflammation

Masayuki Umemura 1, Takaya Kawabe 2, Koyo Shudo 2, Hiroyasu Kidoya 2, Masayuki Fukui 2, Masahide Asano 3, Yoichiro Iwakura 4, Goro Matsuzaki 5, Ryu Imamura 2, Takashi Suda 2*

1 Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan; Center of Molecular Biosciences, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan
2 Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan
3 Department of Transgenic Animal Science, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan
4 Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo 108-8639, Japan
5 Center of Molecular Biosciences, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan

* To whom correspondence should be addressed. E-mail: sudat{at}kenroku.kanazawa-u.ac.jp.


  Abstract

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-1{beta}. 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-1{beta} but also IL-6, IL-17, IL-18, KC/chemokine CXC ligand 1 and macrophage inflammatory protein (MIP)-2, but not of IL-1{alpha}, IFN-{gamma}, TGF-{beta} or TNF-{alpha}. The FFL-induced cytokine production was not observed in Fas-deficient lpr mice. Among cells transfected to express individually IL-1{beta}, IL-6, IL-17, or IL-18, only those expressing IL-1{beta} 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-1{beta}.

Keywords: cytokines; inflammation; rodent; T lymphocytes; tumor immunity.

M. Umemura and T. Kawabe contributed equally to this work


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