Fas ligand induces cell-autonomous IL-23 production in dendritic cells, a mechanism for Fas ligand-induced IL-17 production.
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-1beta 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-1beta Ab strongly inhibited the IL-17-inducing activity. However, rIL-1beta 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-1beta 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.
Kidoya
Hiroyasu
H
Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Umemura
Masayuki
M
Kawabe
Takaya
T
Matsuzaki
Goro
G
Yahagi
Ayano
A
Imamura
Ryu
R
Suda
Takashi
T
D000818:Animals; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000378:metabolism*; D053222:Fas Ligand Protein; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D010537:Peritoneum / Q000166:cytology; D014407:Tumor Cells, Cultured / Q000166:cytology; D048069:Tumor Necrosis Factors / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors