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

Abstract

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-1β 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-1β Ab strongly inhibited the IL-17-inducing activity. However, rIL-1β 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-1β 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.

IL-17-Mediated Regulation of Innate and Acquired Immune Response against Pulmonary Mycobacterium bovis Bacille Calmette-Guérin Infection

“…2B). We also found that IL-23 but not IL-12 induced IL-17 production in resident peritoneal exudate cells (44). To further confirm the importance of IL-23 in the induction of IL-17 after M. bovis BCG i.t.…”

Stimulation of the Intracellular Bacterial Sensor NOD2 Programs Dendritic Cells to Promote Interleukin-17 Production in Human Memory T Cells

“…Altogether, these data support the concept that the development of IL-17 in T cells in mice can be initiated by the TGF-b-IL-6 pathway, but that the induction of fully functional Th17 cells that are protective against bacterial infection or progressors of chronic inflammatory disease depends on IL-23. In addition to IL-23, protection against bacteria requires IL-1 (Zwijnenburg et al, 2003;Miller et al, 2006), which may be explained by the finding that IL-1b and IL-1a synergize with IL-23 in the induction of protective IL-17 by murine Th cells (Kidoya et al, 2005;Sutton et al, 2006).…”

“…However, in humans, this finding has not been confirmed thus far. In addition, both in mice and man, Th17 cells can be induced in memory Th cells by IL-23 (Harrington et al, 2005;Park et al, 2005;Langrish et al, 2005;Aggarwal et al, 2003) and IL-1 (Kidoya et al, 2005;Sutton et al, 2006). The importance of this IL-23-IL-17 axis in antimicrobial immunity is underlined by previous studies showing that protection against Klebsiella pneumoniae (Happel et al, 2005) and Streptococcus pneumoniae (Malley et al, 2006), for example, is impaired in mice deficient in the IL-23-specific subunit p19 or in IL-17.…”

Fas-Mediated Inflammatory Response inListeria monocytogenesInfection

“…In addition, Miwa et al (3) and our group have shown that innate inflammatory cytokines such as IL-18 and IL-1b are produced from neutrophils and macrophages via Fas signaling without the induction of apoptosis (4). Furthermore, it has been shown that the production of other cytokines or chemokines is also induced by Fas stimulation (5)(6)(7)(8)(9)(10). These data indicate the possibility that Fas signaling plays important roles in the innate immune system in response to infection by pathogenic microbes; however, the precise molecular mechanisms and physiological roles of inflammatory cytokine production via Fas signaling in bacterial infection are not clear.…”