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PNAS 106 (39): 16764-16769

Copyright © 2009 by the National Academy of Sciences.


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

David R. Baumana, Andrew D. Bitmansourb, Jeffrey G. McDonalda, Bonne M. Thompsona, Guosheng Lianga, and David W. Russella,1

aDepartment of Molecular Genetics and bThe Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390

Contributed by David W. Russell, August 12, 2009

Received for publication July 31, 2009.

Abstract: 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 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.

Key Words: adaptive immune system • cholesterol 25-hydroxylase • innate immune system • negative regulation • oxysterol

Author contributions: D.R.B., A.D.B., J.G.M., G.L., and D.W.R. designed research; D.R.B., A.D.B., J.G.M., B.M.T., and G.L. performed research; D.R.B., A.D.B., J.G.M., G.L., and D.W.R. analyzed data; and D.R.B. and D.W.R. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at

1To whom correspondence should be addressed at: Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046. E-mail: david.russell{at}

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