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| Content Provider | frontiers |
|---|---|
| Author | Nagashima, Hiroyuki Ishii, Naoto So, Takanori |
| Abstract | There is growing evidence that tumor necrosis factor (TNF) receptor-associated factors (TRAFs) bind to unconventional membrane-bound receptors in many cell types and control their key signaling activity, in both positive and negative ways. TRAFs function in a variety of biological processes in health and disease, and dysregulation of TRAF expression or activity often leads to a patho-physiological outcome. We have identified a novel attribute of TRAF2 and TRAF5 in interleukin-6 (IL-6) receptor signaling in CD4+ T cells. TRAF2 and TRAF5 are highly expressed by naïve CD4+ T cells and constitutively bind to the signal-transducing receptor common chain gp130 via the C-terminal TRAF domain. The binding between TRAF and gp130 limits the early signaling activity of the IL-6 receptor complex by preventing proximal interaction of Janus kinases (JAKs) associated with gp130. In this reason, TRAF2 and TRAF5 in naïve CD4+ T cells negatively regulate IL-6-mediated activation of signal transducer and activator of transcription 3 (STAT3) that is required for the development of IL-17-secreting CD4+ TH17 cells. Indeed, Traf2-knockdown in differentiating Traf5-/- CD4+ T cells strongly promotes TH17 development. Traf5-/- donor CD4+ T cells exacerbate the development of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in wild-type recipient mice. In this review, we summarize the current understanding of the role for TRAF2 and TRAF5 in the regulation of IL-6-driven differentiation of pro-inflammatory CD4+ T cells, especially focusing on the molecular mechanism by which TRAF2 and TRAF5 inhibit the JAK-STAT pathway that is initiated in the IL-6 receptor signaling complex. |
| ISSN | 16643224 |
| DOI | 10.3389/fimmu.2018.01986 |
| Volume Number | 9 |
| Journal | Frontiers in Immunology |
| Language | English |
| Publisher Date | 2018-08-30 |
| Access Restriction | Open |
| Subject Keyword | Th17 IL-6 Inflammation TRAF2 TRAF5 Autoimmunity |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
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