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Fas Ligand Induces Cell-Autonomous IL-23 Production in Dendritic Cells, a Mechanism for Fas Ligand-Induced IL-17 Production¹

Hiroyasu Kidoya^2,*, Masayuki Umemura^2,*,, Takaya Kawabe^*, Goro Matsuzaki, Ayano Yahagi, Ryu Imamura^* and Takashi Suda^3,*

^* Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; and Center of Molecular Biosciences, University of the Ryukyus, Okinawa, Japan

Fas ligand (FasL) has the potential to induce inflammation accompanied by massive neutrophil infiltration. We previously reported that FasL rapidly induces the production of various inflammatory cytokines including IL-1 and IL-17. In this study, we investigated the mechanism of the FasL-induced IL-17 production. We found that the culture supernatant of mouse resident peritoneal exudate cells (PEC) cocultured with FasL-expressing tumor (FFL) cells induced IL-17 production in freshly isolated resident PEC. Anti-IL-1 Ab strongly inhibited the IL-17-inducing activity. However, rIL-1 by itself induced only weak IL-17 production. Intriguingly, anti-IL-12 Ab but not an IL-15-neutralizing agent, IL15R-Fc, strongly inhibited the FasL-induced IL-17-inducing activity. IL-23, which shares the p40 subunit with IL-12, but not IL-12 itself, induced IL-17 production synergistically with IL-1 in resident PEC. FasL induced the production of IL-23 in PEC in vivo and in vitro, and IL-17 production following the i.p. injection of FFL cells was severely impaired in p40^–/– mice, indicating that IL-23 plays an important role in the FasL-induced IL-17 production. FFL also induced the production of IL-23 in bone marrow- or PEC-derived dendritic cells (DCs). Finally, FasL induced only weak p40 production in a mixture of p40^–/– and Fas^–/– DC, indicating that FasL induces IL-23 production in DC mainly in a cell-autonomous manner.

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