Receptor cross-talk spatially restricts p-ERK during TLR4 stimulation of autoreactive B cells.
Receptor cross-talk spatially restricts p-ERK during TLR4 stimulation of autoreactive B cells.
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TLR4 刺激自身反应性 B 细胞期间，受体串扰在空间上限制 p-ERK。
DOI：
10.4049/jimmunol.1200940
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发表时间：
2012-10-15
期刊：
影响因子：
--
通讯作者：
Vilen BJ
中科院分区：
文献类型：
--
作者：
Lee SR;Rutan JA;Monteith AJ;Jones SZ;Kang SA;Krum KN;Kilmon MA;Roques JR;Wagner NJ;Clarke SH;Vilen BJ
To maintain tolerance, autoreactive B cells must regulate signal transduction from the B cell receptor and Toll-like receptors. We recently identified that dendritic cells and macrophages regulate autoreactive cells during TLR4 activation by releasing IL-6 and soluble CD40L (sCD40L). These cytokines selectively repress antibody secretion from autoreactive, but not antigenically naïve, B cells. How IL-6 and sCD40L repress autoantibody production is unknown. In this paper, we show that IL-6 and sCD40L are required for low-affinity/avidity autoreactive B cells to maintain tolerance through a mechanism involving receptor crosstalk between the BCR, TLR4, and the IL-6 receptor or CD40. We show that acute signaling through IL-6 receptor or CD40 integrates with chronic BCR-mediated ERK activation to restrict pERK from the nucleus and repress TLR4-induced Blimp-1 and XBP-1 expression. Tolerance is disrupted in 2-12H/MRL/lpr mice where IL-6 and sCD40L fail to spatially restrict pERK and fail to repress TLR4-induced Ig secretion. In the case of CD40, acute signaling in B cells from 2-12H/MRL/lpr mice is intact, but the chronic activation of pERK emanating from the BCR is attenuated. Re-establishing chronically active ERK through retroviral expression of constitutively active MEK1 restores tolerance upon sCD40L, but not IL-6, stimulation indicating that regulation by IL-6 requires another signaling effector. These data define the molecular basis for the regulation of low-affinity autoreactive B cells during TLR4 stimulation, they explain how autoreactive but not naïve B cells are repressed by IL-6 and sCD40L, and they identify B cell defects in lupus-prone mice that lead to TLR4-induced autoantibody production.
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影响因子：
3.9
作者：
Andreadi, Catherine;Noble, Catherine;Pritchard, Catrin
通讯作者：
Pritchard, Catrin
影响因子：
16
作者：
Dougherty, Michele K.;Ritt, Daniel A.;Zhou, Ming;Specht, Suzanne I.;Monson, Daniel M.;Veenstra, Timothy D.;Morrison, Deborah K.
通讯作者：
Morrison, Deborah K.
影响因子：
4.4
作者：
Kilmon, MA;Rutan, JA;Vilen, BJ
通讯作者：
Vilen, BJ
DOI：
10.1084/jem.186.11.1923
发表时间：
1997-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Inaoki M;Sato S;Weintraub BC;Goodnow CC;Tedder TF
通讯作者：
Tedder TF
影响因子：
4.4
作者：
Lartigue, Aurelia;Colliou, Natacha;Musette, Philippe
通讯作者：
Musette, Philippe