title: STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice.
abstract: IL-23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 has proinflammatory activity, inducing IL-17 secretion from activated CD4(+) T cells and stimulating the proliferation of memory CD4(+) T cells. We investigated the pathogenic role of IL-23 in CD4(+) T cells in mice lacking the IL-1R antagonist (IL-1Ra(-/-)), an animal model of spontaneous arthritis. IL-23 was strongly expressed in the inflamed joints of IL-1Ra(-/-) mice. Recombinant adenovirus expressing mouse IL-23 (rAd/mIL-23) significantly accelerated this joint inflammation and joint destruction. IL-1beta further increased the production of IL-23, which induced IL-17 production and OX40 expression in splenic CD4(+) T cells of IL-1Ra(-/-) mice. Blocking IL-23 with anti-p19 Ab abolished the IL-17 production induced by IL-1 in splenocyte cultures. The process of IL-23-induced IL-17 production in CD4(+) T cells was mediated via the activation of Jak2, PI3K/Akt, STAT3, and NF-kappaB, whereas p38 MAPK and AP-1 did not participate in the process. Our data suggest that IL-23 is a link between IL-1 and IL-17. IL-23 seems to be a central proinflammatory cytokine in the pathogenesis of this IL-1Ra(-/-) model of spontaneous arthritis. Its intracellular signaling pathway could be useful therapeutic targets in the treatment of autoimmune arthritis.
authors.affiliation: The Rheumatism Research Center, Catholic Research Institute of Medical Science, Catholic University of Korea, 505 Banpo-Dong, Seocho-Ku, 137-040 Seoul, Korea.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Kang
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Moon
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Nam
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Jhun
authors.forename: Seong-Beom
authors.initials: SB
authors.lastname: Heo
authors.forename: Hyun-Tak
authors.initials: HT
authors.lastname: Jin
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Min
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Kyung-Su
authors.initials: KS
authors.lastname: Park
authors.forename: Young-Gyu
authors.initials: YG
authors.lastname: Cho
authors.forename: Chong-Hyeon
authors.initials: CH
authors.lastname: Yoon
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C507764:Il1rn protein, mouse; C508841:Il23a protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D012795:Sialoglycoproteins