Journal Article

Regulation of Interleukin-6 Receptor Signaling by TNF Receptor-Associated Factor 2 and 5 During Differentiation of Inflammatory CD4+ T Cells

So, Takanori, Ishii, Naoto, Nagashima, Hiroyuki

2018

Overview

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 T 17 cells. Indeed, -knockdown in differentiating CD4 T cells strongly promotes T 17 development. 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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Antigens / autoimmunity / CD4 antigen / Cell activation / Cell differentiation / Cells / Cytokines / Experimental allergic encephalomyelitis / Glycoprotein gp130 / Helper cells / IL-6 / Immunology / Inflammation / Interleukin 6 / Interleukin 6 receptors / Kinases / Lymphocytes / Lymphocytes T / Molecular modelling / Phosphorylation / Proteins / Signal transduction / Stat3 protein / TH17 / TRAF2 / TRAF2 protein / TRAF5 / Tumor necrosis factor / Tumor necrosis factor receptors / Tumor necrosis factor-TNF