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

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.

Pubmed ID: 19805370


  • Bauman DR
  • Bitmansour AD
  • McDonald JG
  • Thompson BM
  • Liang G
  • Russell DW


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

Publication Data

September 29, 2009

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK 07745
  • Agency: NIGMS NIH HHS, Id: GM 069338
  • Agency: NHLBI NIH HHS, Id: HL 20848

Mesh Terms

  • Animals
  • B-Lymphocytes
  • Cytokines
  • Hydroxycholesterols
  • Immunoglobulin A
  • Macrophages
  • Mice
  • Mice, Transgenic
  • Steroid Hydroxylases
  • Toll-Like Receptors