Abstract
Abstract Dysregulation in Toll-like receptor (TLR) signaling has been implicated in various inflammatory and autoimmune disorders. The cytoplasmic adaptor proteins TNF receptor associated factor (TRAF)3 and TRAF6 are known to mediate TLR signaling. Data from our lab suggest for the first time that another family member, TRAF5, is a negative regulator of TLR signaling. B lymphocytes, macrophages, and dendritic cells from TRAF5-/- mice have enhanced early signaling pathways including increased phosphorylation of the kinases ERK1/2, JNK, and Akt . They also produce more cytokines after TLR ligation. Consistent with these results, overexpression of TRAF5 in B cells inhibits TLR-induced cytokine production. Pursuing the mechanism of TRAF5-mediated regulation, we discovered that TRAF5 negatively regulates the transcription and protein levels of TRAF6. Additionally, TRAF5 associates in a complex with TRAF3, TRAF6, and the TLR adaptor protein MyD88 after TLR stimulation in B cells. Results suggest multiple mechanisms by which TRAF5 negatively regulates TLR signaling. TRAF5 deficiency has been reported to accelerate atherogenesis in mice. Elucidating the role of TRAF5 in TLR signaling may thus provide a new target for therapies against a variety of inflammatory conditions.
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