Epigenetic regulation of established human type 1 versus type 2 cytokine responses Ruey-Chyi Su, PhD, Allan B. Becker, MD, Anita L. Kozyrskyj, PhD, Kent.

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Presentation transcript:

Epigenetic regulation of established human type 1 versus type 2 cytokine responses Ruey-Chyi Su, PhD, Allan B. Becker, MD, Anita L. Kozyrskyj, PhD, Kent T. HayGlass, PhD Journal of Allergy and Clinical Immunology Volume 121, Issue 1, Pages 57-63.e3 (January 2008) DOI: 10.1016/j.jaci.2007.09.004 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Polyclonal activator PHA selectively activates CD45RO+ T cells. CD45RO+ and CD45RA+ T-cell subsets were stimulated with PHA for 22 hours. Culture supernatants were assayed for IL-13, IL-5, IFN-γ, and CXCL-10 by using ELISA. Culture medium alone did not yield detectable amounts of cytokine/chemokine. Results (mean values of triplicates, with SEMs) are shown for 1 representative individual of 5 studied. Journal of Allergy and Clinical Immunology 2008 121, 57-63.e3DOI: (10.1016/j.jaci.2007.09.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The effect of inhibiting HDAC activity on cytokine responses in PHA-stimulated ex vivo PBMCs. PBMCs were treated with TSA before PHA stimulation. A, At 22 hours poststimulation, cellular mRNA of Il4, Il13, and Ifnγ genes were examined with semiquantitative RT-PCR. cDNA from PBMCs treated with PHA and TSA (except for Ifnγ, where PHA-stimulated sample was used) were titrated to demonstrate the linearity of PCR. These 4 are representative of 12 individuals examined. B, Culture supernatants were assayed by ELISA for IL-5, IL-13, IL-10, IL-2, IFN-γ, and CXCL-10 at 22 hours. Journal of Allergy and Clinical Immunology 2008 121, 57-63.e3DOI: (10.1016/j.jaci.2007.09.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 The effect of inhibiting HDAC activity on the balance of TH1/TH2-associated responses to PHA stimulation. TSA effect on the balance of TH1/TH2-associated responses was calculated as ratios of TH1 (IFN-γ, CXCL-10, or IL-2) versus TH2 (IL-13 or IL-5) cytokine production. Each dot represents an individual studied, with medians (∗ and bars) also indicated (n = 58). Journal of Allergy and Clinical Immunology 2008 121, 57-63.e3DOI: (10.1016/j.jaci.2007.09.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Inhibition of HDAC shifts TSST-1–stimulated TH1-like recall responses toward TH2-like immunity. PBMCs were incubated with TSA before TSST-1 stimulation. A, Culture supernatants were assayed for IFN-γ and IL-13. B, The ratio of IFN-γ versus IL-13 was calculated as in Fig 3. Each dot represents an individual studied, with medians also indicated (n = 8). Journal of Allergy and Clinical Immunology 2008 121, 57-63.e3DOI: (10.1016/j.jaci.2007.09.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Inhibition of HDAC activity increases Gata-3 and Sphk1 expression. A, Gata-3 expression was analyzed against endogenous Gapdh with real-time RT-PCR (Applied Biosystems) with culture media as a reference (n = 6). Medians are shown in the graph. B, T-bet and Sphk1 transcripts were examined with semiquantitative RT-PCR. cDNA from PBMCs treated with PHA and TSA were titrated to show the linearity of PCR. These 4 are representative of 12 individuals examined. Journal of Allergy and Clinical Immunology 2008 121, 57-63.e3DOI: (10.1016/j.jaci.2007.09.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Effect of TSA on cellular histone acetylation and endogenous HDAC activity. A, Histone H4–enriched nuclear extracts, prepared from human PBMCs treated with TSA or media alone, were blotted for acetylated histone H4 and unmodified histone H4. B, HDAC activity in nuclear extracts of PBMCs treated with or without TSA were measured 22 hours postculture. Percentage inhibition was calculated with reference to PBMCs not treated with TSA. Journal of Allergy and Clinical Immunology 2008 121, 57-63.e3DOI: (10.1016/j.jaci.2007.09.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Quantification of changes in Ifnγ and Il13 mRNA expression on TSA inhibition of cellular HDAC activity. RNA was extracted 22 hours poststimulation. Transcripts of Ifnγ and Il13 were analyzed against endogenous Gapdh expression with real-time RT-PCR. Fold increases in Ifnγ and Il13 transcription were calculated with the ΔΔ Ct program (Applied Biosystems, Foster City, Calif) by using CM as a baseline reference. ∗P = .01; ∗∗P = .0018; ∗∗∗P < .0001; n = 6. Journal of Allergy and Clinical Immunology 2008 121, 57-63.e3DOI: (10.1016/j.jaci.2007.09.004) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions