Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
J Immunol. 2010 Mar 1;184(5):2289-96. doi: 10.4049/jimmunol.0903133. Epub 2010 Feb 5.
We previously identified that autoreactive B cells from BXD2 mice can be targeted by IL-17, leading to upregulation of the expression of regulators of G-protein signaling (Rgs) genes that facilitated the development of spontaneous germinal centers. Little is known about the signaling pathway used by IL-17 to upregulate RGS. In the current study, we found that IL-17 rapidly activates the canonical NF-kappaB signaling pathway and that BXD2 B cells exhibit higher basal and activated phosphorylated p65 levels than B6 or BXD2-Il17ra(-/-) B cells. Inhibition of p65 phosphorylation downregulated RGS16 expression and abrogated the IL-17-induced chemotactic arrest of B cells in response to CXCL12. Knockdown of TNFR-associated factor 6 or NF-kappaB activator 1 in 70Z/3 pre-B cells led to decreased Rgs16 expression, indicating that both of these two genes are involved in IL-17-mediated activation of NF-kappaB signaling in B cells. These findings identify the signaling pathway regulated by IL-17 to contribute to the development of spontaneous germinal centers in autoimmune BXD2 mice.
我们之前发现，BXD2 小鼠的自身反应性 B 细胞可被白介素-17（IL-17）靶向，从而上调 G 蛋白信号调节因子（RGS）基因的表达，促进自发生发中心的形成。目前对于 IL-17 用来上调 RGS 的信号通路知之甚少。在本研究中，我们发现 IL-17 可快速激活经典的 NF-κB 信号通路，且 BXD2 B 细胞的基础和激活的磷酸化 p65 水平高于 B6 或 BXD2-Il17ra（-/-）B 细胞。抑制 p65 磷酸化可下调 RGS16 的表达，并消除 IL-17 诱导的 B 细胞对 CXCL12 的趋化性阻滞。在 70Z/3 前 B 细胞中敲低 TNFR 相关因子 6 或 NF-κB 激活物 1 可导致 Rgs16 表达降低，表明这两种基因均参与 IL-17 介导的 B 细胞 NF-κB 信号通路的激活。这些发现确定了由 IL-17 调节的信号通路有助于自身免疫性 BXD2 小鼠自发生发中心的形成。
