25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production
25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production
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DOI：
10.1073/pnas.0909142106
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发表时间：
2009-09-29
影响因子：
11.1
通讯作者：
Russell, David W.
中科院分区：
文献类型：
--
作者：
Bauman, David R.;Bitmansour, Andrew D.;Russell, David W.
25-羟基胆固醇在哺乳动物组织中产生。这种氧化甾醇的功能尚不清楚。在这里，我们描述了25-羟基胆固醇在调节免疫系统中的核心作用。在最初的实验中，我们发现刺激巨噬细胞toll样受体（TLR）可诱导胆固醇25-羟化酶的表达和25-羟基胆固醇的合成。用纳米摩尔浓度的25-羟基胆固醇处理幼稚B细胞可抑制il -2介导的B细胞增殖刺激，抑制激活诱导的胞苷脱氨酶（AID）表达，阻断类开关重组，导致IgA产量显著降低。与这些发现一致，小鼠胆固醇25-羟化酶基因的缺失导致血清IgA的增加。相反，CYP7B1羟化酶（可降解25-羟基胆固醇）失活可降低血清IgA。巨噬细胞来源的甾醇在TLR激活下抑制B细胞中的IgA类转换，为先天免疫系统对适应性免疫反应的局部和全身负调控提供了一种机制。
25-Hydroxycholesterol is produced in mammalian tissues. The function of this oxysterol is unknown. Here we describe a central role for 25-hydroxycholesterol in regulating the immune system. In initial experiments, we found that stimulation of macrophage Toll-like receptors (TLR) induced expression of cholesterol 25-hydroxylase and the synthesis of 25-hydroxycholesterol. Treatment of naive B cells with nanomolar concentrations of 25-hydroxycholesterol suppressed IL-2-mediated stimulation of B cell proliferation, repressed activation-induced cytidine deaminase (AID) expression, and blocked class switch recombination, leading to markedly decreased IgA production. Consistent with these findings, deletion of the mouse cholesterol 25-hydroxylase gene caused an increase in serum IgA. Conversely, inactivation of the CYP7B1 oxysterol 7 alpha-hydroxylase, which degrades 25-hydroxycholesterol, decreased serum IgA. The suppression of IgA class switching in B cells by a macrophage-derived sterol in response to TLR activation provides a mechanism for local and systemic negative regulation of the adaptive immune response by the innate immune system.