4.6 Article

TRAF5 Negatively Regulates TLR Signaling in B Lymphocytes

Journal

JOURNAL OF IMMUNOLOGY
Volume 192, Issue 1, Pages 145-150

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301901

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Funding

  1. National Institutes of Health [R01AI28847]
  2. Department of Veterans Affairs [1I01BX001702]
  3. Roy J. and Lucille A. Carver Charitable Trust

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The cytoplasmic adaptor proteins TNFR-associated factor (TRAF) 3 and TRAF6 are important mediators of TLR signaling. To our knowledge, we show in this study for the first time that another TRAF family member, TRAF5, is a negative regulator of TLR signaling. B lymphocytes from TRAF5(-/-) mice produced more IL-6, IL-12p40, IL-10, TNF-alpha, and IgM than did wild-type B cells after TLR stimulation. Consistent with these data, exogenous overexpression of TRAF5 in B cells inhibited TLR-mediated cytokine and Ab production. TLR stimulation of TRAF5-deficient B cells did not affect cell survival, proliferation, or NF-kappa B activation but resulted in markedly enhanced phosphorylation of the MAPKs ERK1/2 and JNK. TRAF5 negatively regulated TLR signaling in a cell-specific manner, because TRAF5(-/-) macrophages and dendritic cells showed less dramatic differences in TLR-mediated cytokine production than B cells. Following TLR stimulation, TRAF5 associated in a complex with the TLR adaptor protein MyD88 and the B cell-specific positive regulator of TLR signaling TAB2. Furthermore, TRAF5 negatively regulated the association of TAB2 with its signaling partner TRAF6 after TLR ligation in B cells. To our knowledge, these data provide the first evidence that TRAF5 acts as a negative regulator of TLR signaling.

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