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

摘要

Background: Multiple biologic factors influence maintenance of immunologic responsiveness. Here, we studied whether epigenetics has a regulatory function in maintaining pre-established THl-like and TH2-like immunity in human beings. Objective: We focused on delineating the role of endogenous histone deacetylase (HDAC) activity in regulating cytokine recall responses.N Methods: Using RT-PCR and ELISA, the effect of increasing cellular acetylation on TH1/TH2 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 TH2-associated (IL-13, 139%; IL-5, 168%; P < .0001) and reduced TH1 -associated recall responses (IFN-7, 76%; CXCL10, 47%; P < .0001). IL-2 and IL-10 production were reduced 25% to 55% (P < .0001). These alterations in TH2-associated arid THl-associated recall responses were associated with increased expression of Gata-3 and sphingosine kinase 1, a THl-negative regulator, independent of T-bet expression. Overall, inhibition of endogenous HDAC activity shifted TH1:TH2 ratios by 3-fold to 8-fold (P < .0001), skewing recall responses toward a more TH2-like phenotype, independent of the stimulus used. Conclusion: Endogenous HDAC activity plays a crucial role in maintaining the balance of pre-established THl-like and TH2-like responses, inhibiting excessive TH2 immunity. (J Allergy Clin Immunol 2008;121:57-63.)#