Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 106 (39): 16764-16769

Copyright © 2009 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / IMMUNOLOGY

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 www.pnas.org/cgi/content/full/0909142106/DCSupplemental.

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}utsouthwestern.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
25-Hydroxycholesterol Activates the Integrated Stress Response to Reprogram Transcription and Translation in Macrophages.
N. Shibata, A. F. Carlin, N. J. Spann, K. Saijo, C. S. Morello, J. G. McDonald, C. E. Romanoski, M. R. Maurya, M. U. Kaikkonen, M. T. Lam, et al. (2013)
J. Biol. Chem. 288, 35812-35823
   Abstract »    Full Text »    PDF »
Naive B-cell trafficking is shaped by local chemokine availability and LFA-1-independent stromal interactions.
F. M. Coelho, D. Natale, S. F. Soriano, M. Hons, J. Swoger, J. Mayer, R. Danuser, E. Scandella, M. Pieczyk, H.-G. Zerwes, et al. (2013)
Blood 121, 4101-4109
   Abstract »    Full Text »    PDF »
EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture.
T. Yi and J. G. Cyster (2013)
eLife Sci 2, e00757
   Abstract »    Full Text »    PDF »
A comprehensive method for extraction and quantitative analysis of sterols and secosteroids from human plasma.
J. G. McDonald, D. D. Smith, A. R. Stiles, and D. W. Russell (2012)
J. Lipid Res. 53, 1399-1409
   Abstract »    Full Text »    PDF »
ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation.
E. S. Gold, S. A. Ramsey, M. J. Sartain, J. Selinummi, I. Podolsky, D. J. Rodriguez, R. L. Moritz, and A. Aderem (2012)
J. Exp. Med. 209, 807-817
   Abstract »    Full Text »    PDF »
Multicohort Genomewide Association Study Reveals a New Signal of Protection Against HIV-1 Acquisition.
S. Limou, O. Delaneau, D. van Manen, P. An, E. Sezgin, S. Le Clerc, C. Coulonges, J. L. Troyer, J. H. Veldink, L. H. van den Berg, et al. (2012)
The Journal of Infectious Disease 205, 1155-1162
   Abstract »    Full Text »    PDF »
Still another activity by the highly promiscuous enzyme CYP3A4: 25-hydroxylation of cholesterol.
U. Diczfalusy and I. Bjorkhem (2011)
J. Lipid Res. 52, 1447-1449
   Full Text »    PDF »
Cholesterol 25-hydroxylation activity of CYP3A.
A. Honda, T. Miyazaki, T. Ikegami, J. Iwamoto, T. Maeda, T. Hirayama, Y. Saito, T. Teramoto, and Y. Matsuzaki (2011)
J. Lipid Res. 52, 1509-1516
   Abstract »    Full Text »    PDF »
X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C.
O. M. Siggs, B. Schnabl, B. Webb, and B. Beutler (2011)
PNAS 108, 7890-7895
   Abstract »    Full Text »    PDF »
Listeria monocytogenes Infection Induces Prosurvival Metabolic Signaling in Macrophages.
T. Zou, O. Garifulin, R. Berland, and V. L. Boyartchuk (2011)
Infect. Immun. 79, 1526-1535
   Abstract »    Full Text »    PDF »
A Mouse Macrophage Lipidome.
E. A. Dennis, R. A. Deems, R. Harkewicz, O. Quehenberger, H. A. Brown, S. B. Milne, D. S. Myers, C. K. Glass, G. Hardiman, D. Reichart, et al. (2010)
J. Biol. Chem. 285, 39976-39985
   Abstract »    Full Text »    PDF »
Editorial: 25-Hydroxycholesterol: a new life in immunology.
J. G. McDonald and D. W. Russell (2010)
J. Leukoc. Biol. 88, 1071-1072
   Full Text »    PDF »
Cholesterol 25-hydroxylase production by dendritic cells and macrophages is regulated by type I interferons.
K. Park and A. L. Scott (2010)
J. Leukoc. Biol. 88, 1081-1087
   Abstract »    Full Text »    PDF »
CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance.
J. M. Brown, J. L. Betters, C. Lord, Y. Ma, X. Han, K. Yang, H. M. Alger, J. Melchior, J. Sawyer, R. Shah, et al. (2010)
J. Lipid Res. 51, 3306-3315
   Abstract »    Full Text »    PDF »
Genetic connections between neurological disorders and cholesterol metabolism.
I. Bjorkhem, V. Leoni, and S. Meaney (2010)
J. Lipid Res. 51, 2489-2503
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882