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PMID: 19805370 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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 ·Vol. 106 ·No. 39 ·2009-09-29 ·Pages 16764-9

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

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 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.

MeSH Terms
Animals B-Lymphocytes/metabolism Cytokines/metabolism Hydroxycholesterols/metabolism Immunoglobulin A/biosynthesis Macrophages/metabolism Mice Mice, Transgenic Steroid Hydroxylases/genetics,metabolism Toll-Like Receptors/metabolism
Chemicals
Cytokines Hydroxycholesterols Immunoglobulin A Toll-Like Receptors 25-hydroxycholesterol Steroid Hydroxylases cholesterol 25-hydroxylase
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Bauman David R
Department of Molecular Genetics and The Cancer Immunobiology Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Bitmansour Andrew D
McDonald Jeffrey G
Thompson Bonne M
Liang Guosheng
Russell David W
References (33)
33 references, click to expand
  1. Toll-like receptor 5-deficient mice have dysregulated intestinal gene expression and nonspecific resistance to Salmonella-induced typhoid-like disease.
    Infect Immun. 2008 Mar;76(3):1276-81 PMID: 18195036
  2. B cell differentiation and isotype switching is related to division cycle number.
    J Exp Med. 1996 Jul 1;184(1):277-81 PMID: 8691143
  3. Inferences, questions and possibilities in Toll-like receptor signalling.
    Nature. 2004 Jul 8;430(6996):257-63 PMID: 15241424
  4. Estrogen directly activates AID transcription and function.
    J Exp Med. 2009 Jan 16;206(1):99-111 PMID: 19139166
  5. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI.
    Nat Immunol. 2007 Mar;8(3):294-303 PMID: 17259987
  6. TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and -independent humoral immune responses.
    PLoS One. 2009;4(3):e4736 PMID: 19270748
  7. Interleukins and IgA synthesis. Human and murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells.
    J Exp Med. 1989 Jun 1;169(6):2133-48 PMID: 2786548
  8. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair.
    Nat Rev Immunol. 2004 Jul;4(7):541-52 PMID: 15229473
  9. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.
    J Clin Invest. 1998 Nov 1;102(9):1690-703 PMID: 9802883
  10. Role of J chain in secretory immunoglobulin formation.
    Scand J Immunol. 2000 Sep;52(3):240-8 PMID: 10972899
  11. Mechanism for transforming growth factor beta and IL-2 enhancement of IgA expression in lipopolysaccharide-stimulated B cell cultures.
    J Immunol. 1990 Feb 1;144(3):952-9 PMID: 2295822
  12. Disruption of the oxysterol 7alpha-hydroxylase gene in mice.
    J Biol Chem. 2000 Jun 2;275(22):16536-42 PMID: 10748048
  13. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.
    Nat Rev Immunol. 2008 May;8(5):349-61 PMID: 18437155
  14. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene.
    Science. 1998 Dec 11;282(5396):2085-8 PMID: 9851930
  15. Mice refractory to lipopolysaccharide manifest high immunoglobulin A responses to orally administered antigen.
    Infect Immun. 1980 Aug;29(2):322-8 PMID: 7216415
  16. Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol.
    Cell Metab. 2005 Mar;1(3):179-89 PMID: 16054061
  17. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.
    Nature. 1996 Oct 24;383(6602):728-31 PMID: 8878485
  18. The biology of intestinal immunoglobulin A responses.
    Immunity. 2008 Jun;28(6):740-50 PMID: 18549797
  19. Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide.
    J Lipid Res. 2009 Nov;50(11):2258-64 PMID: 19502589
  20. Limiting inflammatory responses during activation of innate immunity.
    Nat Immunol. 2005 Dec;6(12):1198-205 PMID: 16369559
  21. Identification and characterization of a mouse oxysterol 7alpha-hydroxylase cDNA.
    J Biol Chem. 1997 Sep 19;272(38):23995-4001 PMID: 9295351
  22. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.
    Cell. 2000 Sep 1;102(5):553-63 PMID: 11007474
  23. Differential regulation of IgA production by TGF-beta and IL-5: TGF-beta induces surface IgA-positive cells bearing IL-5 receptor, whereas IL-5 promotes their survival and maturation into IgA-secreting cells.
    Cell Immunol. 1992 Mar;140(1):158-72 PMID: 1739984
  24. The immune geography of IgA induction and function.
    Mucosal Immunol. 2008 Jan;1(1):11-22 PMID: 19079156
  25. Cellular basis for elevated IgA responses in C3H/HeJ mice.
    J Immunol. 1980 Aug;125(2):732-7 PMID: 6967087
  26. Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence.
    Nat Rev Immunol. 2008 Oct;8(10):764-75 PMID: 18825130
  27. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL.
    Immunity. 2007 Jun;26(6):812-26 PMID: 17570691
  28. Immune modulating therapy for IgA nephropathy: rationale and evidence.
    Semin Nephrol. 2008 Jan;28(1):38-47 PMID: 18222345
  29. Innate immunity of the gut: mucosal defense in health and disease.
    J Pediatr Gastroenterol Nutr. 2004 May;38(5):463-73 PMID: 15097431
  30. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.
    Science. 2006 Mar 24;311(5768):1770-3 PMID: 16497887
  31. Mechanism and regulation of class switch recombination.
    Annu Rev Immunol. 2008;26:261-92 PMID: 18370922
  32. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2).
    Cell. 2000 Sep 1;102(5):565-75 PMID: 11007475
  33. The regulation of IgA class switching.
    Nat Rev Immunol. 2008 Jun;8(6):421-34 PMID: 18483500
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0909142106
Published
2009-09-29
Epub
2009-00-15
Pages
16764-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2757821
Subset
IM
Grants
NIGMS NIH HHS · GM 069338 · United States
NIDDK NIH HHS · T32 DK007745 · United States
NIGMS NIH HHS · U54 GM069338 · United States
NHLBI NIH HHS · HL 20848 · United States
NIDDK NIH HHS · DK 07745 · United States
External Links
PubMed source DOI: 10.1073/pnas.0909142106 PMC Full Text View journal details
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