Furthermore, we found that enforced expression of IL-23R in T cells enhanced the type 2 immune responses in allergic airway inflammation. differentiate to a prevailing Th2 effector phenotype which predominantly secret interleukin-4 (IL-4), IL-5, and IL-13. Furthermore, these cytokines induce the recruitment of eosinophils, mast QL47 cells and lymphocytes, hyperplasia of smooth muscle and goblet cells, and airway hyperresponsiveness, which are often associated with increased serum IgE concentration13. Interleukin-23 (IL-23) is a member of the IL-12 family of heterodimeric cytokines. It is composed of a unique p19 subunit and a common p40 subunit sharing with IL-124. IL-23 binds to a heterodimeric receptor composed of the IL-12 receptor 1 (IL-12R1) and IL-23 receptor (IL-23R) and this subsequently activates Jak2, Tyk2, and signal transducers and activators of transcription (STATs) 1, 3, 4, and 55. As IL-12, IL-23 is primarily secreted by activated DCs, monocytes and macrophages6. It has been shown that IL-23 is important in some inflammatory diseases including experimental autoimmune encephalitis (EAE), collagen-induced arthritis (CIA), and intestinal inflammation79. Moreover, polymorphisms in the gene encoding the IL-23R are important susceptibility factor for these disorders1012. The proinflammatory features of IL-23 have been linked with T helper 17 (Th17) cell responses, through expansion and/or maintenance of the Th17 cells11. Th17 cells are a recently described T helper subset characterized by production of IL-17 (IL-17A), Rabbit Polyclonal to AP2C IL-17F and IL-2213,14and have been associated with the induction of autoimmune tissue inflammation1517. Moreover, QL47 it has been shown that IL-17 is expressed in the airway of patients with asthma1820. Recently, we showed IL-17 positively while IL-17F negatively regulates allergic airway inflammation21. A recent report revealed dual effects of IL-17 on allergic asthma22. It is required for induction but negatively regulates established asthma. Although many studies have been focused on the IL-23-Th17 QL47 axis, the effect of IL-23 is evidenced in some diseases to be independent of IL-17 production23,24. For instance, anti-IL-17 treatment had little impact on the T cell-mediated colitis, although the colitis was dependent on IL-2324. Furthermore, development of IL23-dependent colitis did not require IL-17 secretion by T cells23. In this context, IL-23 targets not only Th17 cells but also other cell types to modulate inflammatory response25. Recently, Wakashin et al. found IL-23 mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways, which remains in IL-17-deficient mice, suggesting IL-23 may regulate allergic airway inflammation through an IL-17-independent pathway26. Whether IL-23 directly regulates Th2 cell responses is unclear. Here, we found IL-23 deficiencyalleviate airway inflammation by decreasing eosinophil recruitment and Th2 cytokine production, whereas T cell-specific IL-23R transgenic (Tg) overexpression exaggerated Th2 response and enhanced airway inflammation. Notably, allergen-specific Th17 responses were not altered in IL-23-deficient or IL-23 Tg mice compared with their controls. On the other hand, IL-23-IL-23R signaling promoted GATA3 expressionin vitro, but inhibited T-bet expression and enhanced Th2 differentiation. Our results thus indicate an essential role of IL-23-IL-23R signaling in allergic asthma through regulating Th2 differentiation. == Materials and methods == == Mice == Generation of IL-23R transgenic mice. IL-23R cDNA was amplified from a Th17 cell cDNA pool and inserted into phCD2 containing a human CD2 mini-locus27. The transgene construct was isolated by digestion with Xho I and Xba I and microinjected into B6 mice at the Genetic Engineering Mouse Facility at University of Texas M. D. Anderson Cancer Center. Transgenic founders were maintained by breeding with B6 mice. IL-23 alpha subunit p19 target mutant mice were purchased from NIH Mutant Mouse Regional Resource Centers. Homozygous knockout (hereafter referred to as IL-23KO) and wild-type animals on the 129C57BL/6 mixed background were bred and used in experiments. C57BL/6 mice were purchased from the Jackson Laboratory. All animal QL47 experiments were performed using protocols approved by the Institutional Animal Care and Use Committee at the University of Texas M. D. Anderson Cancer Center. == Induction of asthma == Mice were i.p. immunized.