25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production

Proceedings of the National Academy of Sciences of the United States of America - Tập 106 Số 39 - Trang 16764-16769 - 2009
David R. Bauman1, Andrew BitMansour2, Jeffrey G. McDonald3,4, Bonne M. Thompson3,5, Guosheng Liang3, David W. Russell3
1Department of Molecular Genetics and The Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2The Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390
3‡Department of Molecular Genetics and
4The Center for Human Nutrition
5University of Texas Southwestern Medical Center

Tóm tắt

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 7α-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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 106 Số 39

16764-16769

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