IL-13 inhibits Th17 cell development in dendritic cells via down-

IL-13 inhibits Th17 cell development in dendritic cells via down-regulation of Th17 stimulatory cytokines (IL-1, IL-6 and IL-23).[46] Despite the inhibitory effect of GATA-3 on Th17 development, it seems that GATA3 probably promotes Th17 development through inhibition of IL-2, STAT1 and suppressors of cytokine signaling 3 (SOCS3).[47] IL-2 is a T cell growth factor that is critical for Treg development. It effectively inhibits Th17 cell development. Two pivotal transcription factors that BAY 73-4506 cell line mediate IL-2 signaling are STAT5a/b. Therefore IL-2 or STAT5 deficiency is associated with

inhibitory effects of Tregs and expansion of Th17 cells.[48-51] The transcription factor Ets-1, which is a positive regulator of Th1 development, is another negative regulator for Th17 development. Ets-1 deficiency leads to increased Th17 differentiation and promotion of IL-22 and IL-23R messenger RNA (mRNA) levels in response to IL-6 and TGF-β1. It seems that the inhibitory effect of Ets-1 on Th17 cells is through enhancing IL-2 production.[52] In a recent report,

it has been shown that microRNA mir-326 can bind to and prevent translocation of Ets-1 mRNA. Thus, microRNAs can promote Th17 development through inhibition of the Th17 inhibitor, Ets-1.[11-58] It should be noted that the transcriptional repressor protein BCL-6 regulates T cell differentiation BGJ398 by repressing Th2 cells and enhancing follicular Th cells. It is proposed that BCL-6 enhances Th17 differentiation through suppression of Th2 differentiation.[54] Th17 cells are the dominant

pathogenic cellular component in autoimmune inflammatory diseases, including RA.[55] Although the importance of Th17 cells in animal models of arthritis is unquestionable, there are only limited data on the role of Th17 cells and related cytokines in human arthritic diseases. In addition, the characteristics of human Th17 cells have not been fully defined, and there seems to be substantial differences between human and mouse Th17 cells.[56] Functionally, Th17 cells contribute to host defense by having a role in protection against extracellular bacteria. However, their activities are also pivotal in the development of autoimmune diseases under pathologic conditions.[57] The identification of Th17 and IL-17 as a powerful pro-inflammatory cytokine, have Endonuclease focused attention on the role of Th17 cells in RA and other immune-mediated diseases, such as psoriasis, Crohn’s disease and multiple sclerosis.[5, 58] The hyperfunction of Th17 cells is associated with autoimmune diseases, due to the hypersecretion of the pro-inflammatory cytokine IL-17.[59] Studies in rodents, mammalian cell culture systems, as well as clinical settings, support a specific role for IL-17 in promoting RA.[60] Additional supporting evidence came from IL-17 knock-out animals that failed to develop collagen-induced arthritis (CIA).

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