title: Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production.
abstract: IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting IL-17 and IL-22. Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19- and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-γ and TNF-α. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.
authors.affiliation: Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Mingli
authors.initials: M
authors.lastname: Xu
authors.forename: Noriko
authors.initials: N
authors.lastname: Morishima
authors.forename: Izuru
authors.initials: I
authors.lastname: Mizoguchi
authors.forename: Yukino
authors.initials: Y
authors.lastname: Chiba
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
authors.forename: Koji
authors.initials: K
authors.lastname: Yasutomo
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
mesh_terms: D000818:Animals; D003208:Concanavalin A; D016207:Cytokines / Q000096:biosynthesis; D006520:Hepatitis, Animal / Q000276:immunology* / Q000378:metabolism*; D020381:Interleukin-17 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D003208:Concanavalin A; D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D018336:Receptors, Aryl Hydrocarbon; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D000097043:Interleukin-22; C494087:Stat3 protein, mouse; C494091:Stat4 protein, mouse