Ruey-Chyi Su1, Allan B Becker, Anita L Kozyrskyj, Kent T Hayglass. 1. Canadian 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.
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.
Authors: Kanami Orihara; Solomon O Odemuyiwa; William P Stefura; Ramses Ilarraza; Kent T HayGlass; Redwan Moqbel Journal: Immunology Date: 2017-11-03 Impact factor: 7.397
Authors: Robert C Kern; David B Conley; William Walsh; Rakesh Chandra; Atsushi Kato; Anju Tripathi-Peters; Leslie C Grammer; Robert P Schleimer Journal: Am J Rhinol Date: 2008-09-10