Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242;
J Immunol. 2014 Jan 1;192(1):145-50. doi: 10.4049/jimmunol.1301901. Epub 2013 Nov 20.
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-α, 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-κB 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.
细胞质衔接蛋白 TNFR 相关因子 (TRAF)3 和 TRAF6 是 TLR 信号转导的重要介质。据我们所知，本研究首次表明，TRAF 家族的另一个成员 TRAF5 是 TLR 信号转导的负调节剂。TLR 刺激后，TRAF5(-/-)小鼠的 B 细胞产生的 IL-6、IL-12p40、IL-10、TNF-α 和 IgM 比野生型 B 细胞多。与这些数据一致，外源性过表达 TRAF5 可抑制 B 细胞 TLR 介导的细胞因子和 Ab 产生。TRAF5 缺陷 B 细胞的 TLR 刺激不影响细胞存活、增殖或 NF-κB 激活，但导致 MAPK ERK1/2 和 JNK 的磷酸化明显增强。TRAF5 以细胞特异性方式负调控 TLR 信号转导，因为 TRAF5(-/-)巨噬细胞和树突状细胞的 TLR 介导的细胞因子产生差异不如 B 细胞明显。TLR 刺激后，TRAF5 与 TLR 衔接蛋白 MyD88 和 TLR 信号转导的 B 细胞特异性正调节剂 TAB2 形成复合物。此外，TRAF5 负调控 TLR 交联后 TAB2 与其信号伴侣 TRAF6 的结合。据我们所知，这些数据首次提供了 TRAF5 作为 TLR 信号转导负调节剂的证据。
