STAT3 and NF-κB 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-1β 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-κB, 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.

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

“…Phosphorylations of STAT1 and STAT3 at the Tyr701 or Tyr705 residues, respectively, induce their dimerization, nuclear translocation, and DNA binding [6,17]. In our study, IL-27 alone induced tyrosine phosphorylation of STAT1 (Fig.…”

“…It has been reported that IL-12 and IL-23 activate NF-jB in DC and memory CD4 + T cells, respectively [6,23]. In these cells, JAK2 is involved in the activation of NF-jB; JAK2 may activate IKK via the downstream pathways PI3K/Akt [24,25] and/or PKC/c-src [26].…”

“…It also enhances the cytolytic activity of NK cells, thereby promoting antimicrobial defense [4,5]. IL-23 acts on memory T cells and sustains IFN-c production by these cells as well as promotes a novel T cell population (Th17) characterized by the production of IL-17A, IL-17F, TNF-a, and IL-6 [6]. IL-23 is thus essential for the development of inflammatory autoimmune diseases as well as antimicrobial defense [5,6].…”

“…IL-23 acts on memory T cells and sustains IFN-c production by these cells as well as promotes a novel T cell population (Th17) characterized by the production of IL-17A, IL-17F, TNF-a, and IL-6 [6]. IL-23 is thus essential for the development of inflammatory autoimmune diseases as well as antimicrobial defense [5,6]. The function of IL-27 is rather complex; it acts on naive T cells and primes Th1 development in synergy with IL-12; however, at later phases of infection, IL-27 suppresses IFN-c and IL-17A production in Th1 and Th17 cells, respectively [1,3].…”

A novel insertion variant of the human IL-23 receptor-α chain transcript

“…6 Binding of IL-23 to its receptor activates STAT3 and IL-17 production is then induced. [10][11][12][13] Recently, a small number of IL23R splice variants were identified in normal lymphoid cell lines and human tumor cells. 14 This study was recently independently confirmed (Kan et al, personal communication) and together these recent publications describe exon deletion splice variants of the human IL-23 receptor complex.…”