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


CONCLUSIONS
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.
Su
Ruey-Chyi
RC
Canadian Institute for Health Research, National Training Program in Allergy and Asthma Research, Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Becker
Allan B
AB
Kozyrskyj
Anita L
AL
Hayglass
Kent T
KT
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D010835:Phytohemagglutinins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010835:Phytohemagglutinins; C466999:SPHKAP protein, human; C012589:trichostatin A; D017493:Leukocyte Common Antigens; D006655:Histone Deacetylases