Bauman David R, Bitmansour Andrew D, McDonald Jeffrey G, Thompson Bonne M, Liang Guosheng, Russell David W
Department of Molecular Genetics and The Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16764-9. doi: 10.1073/pnas.0909142106. Epub 2009 Sep 15.
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 naïve 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 7alpha-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.
25-羟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。在此，我们描述了25-羟胆固醇在调节免疫系统中的核心作用。在最初的实验中，我们发现巨噬细胞Toll样受体（TLR）的刺激诱导了胆固醇25-羟化酶的表达和25-羟胆固醇的合成。用纳摩尔浓度的25-羟胆固醇处理未活化的B细胞可抑制IL-2介导的B细胞增殖刺激，抑制活化诱导的胞苷脱氨酶（AID）表达，并阻断类别转换重组，导致IgA产生显著减少。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增加。相反，降解25-羟胆固醇的CYP7B1氧化甾醇7α-羟化酶的失活降低了血清IgA。巨噬细胞衍生的甾醇在响应TLR激活时对B细胞中IgA类别转换的抑制为先天免疫系统对适应性免疫反应进行局部和全身负调节提供了一种机制。
