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J Allergy Clin Immunol. 2008 Jan;121(1):57-63.e3. Epub 2007 Nov 5.

Epigenetic regulation of established human type 1 versus type 2 cytokine responses.

Author information

  • 1Canadian Institute for Health Research, National Training Program in Allergy and Asthma Research, Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.

Abstract

BACKGROUND:

Multiple biologic factors influence maintenance of immunologic responsiveness. Here, we studied whether epigenetics has a regulatory function in maintaining pre-established T(H)1-like and T(H)2-like immunity in human beings.

OBJECTIVE:

We focused on delineating the role of endogenous histone deacetylase (HDAC) activity in regulating cytokine recall responses.

METHODS:

Using RT-PCR and ELISA, the effect of increasing cellular acetylation on T(H)1/T(H)2 cytokine expression was systematically examined in 58 children by inhibiting HDAC activity with trichostatin A.

RESULTS:

Phytohemagglutinin activation selectively stimulates antigen-experienced CD45RO+ T cells, eliciting recall cytokine responses. Trichostatin A reduced HDAC activity by approximately 1/3. The resulting cellular hyperacetylation led to increased T(H)2-associated (IL-13, 139%; IL-5, 168%; P < .0001) and reduced T(H)1-associated recall responses (IFN-gamma, 76%; CXCL10, 47%; P < .0001). IL-2 and IL-10 production were reduced 25% to 55% (P < .0001). These alterations in T(H)2-associated and T(H)1-associated recall responses were associated with increased expression of Gata-3 and sphingosine kinase 1, a T(H)1-negative regulator, independent of T-bet expression. Overall, inhibition of endogenous HDAC activity shifted T(H)1:T(H)2 ratios by 3-fold to 8-fold (P < or = .0001), skewing recall responses toward a more T(H)2-like phenotype, independent of the stimulus used.

CONCLUSION:

Endogenous HDAC activity plays a crucial role in maintaining the balance of pre-established T(H)1-like and T(H)2-like responses, inhibiting excessive T(H)2 immunity.

PMID:
17980413
[PubMed - indexed for MEDLINE]
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