Expression of non-secreted IL-4 is associated with HDAC inhibitor-induced cell death, histone acetylation and c-Jun regulation in human gamma/delta T-cells

// Jaydeep Bhat 1,** , Justyna Sosna 1,5,* , Jurgen Fritsch 1,* , Elgar Susanne Quabius 1,2,* , Stefan Schutze 1 , Sebastian Zeissig 3,6,7 , Ole Ammerpohl 4 , Dieter Adam 1 and Dieter Kabelitz 1 1 Institute of Immunology, Christian-Albrechts-University, Kiel, Germany 2 Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University, Kiel, Germany 3 Department of Internal Medicine I, Christian-Albrechts-University, Kiel, Germany 4 Institute of Human Genetics, University Medical Center Schleswig-Holstein Kiel, Christian-Albrechts-University, Kiel, Germany 5 Current address: Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, USA 6 Current address: Department of Medicine I, University Medical Center Dresden, Technical University Dresden, Dresden, Germany 7 Current address: Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, Dresden, Germany * Authors contributed equally ** This work forms part of the Ph.D. thesis of J.B. Correspondence to: Dieter Kabelitz, email: // Keywords : IL-4, apoptosis, necroptosis, HDAC inhibitors, valproic acid, Immunology and Microbiology Section, Immune response, Immunity Received : May 11, 2016 Accepted : August 11, 2016 Published : August 20, 2016 Abstract Previously, the expression of a non-secreted IL-4 variant (IL-4δ 13 ) has been described in association with apoptosis and age-dependent Th2 T-cell polarization. Signaling pathways involved in this process have so far not been studied. Here we report the induction of IL-4δ 13 expression in human γδ T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4δ 13 was associated with increased cytoplasmic IL-4Rα and decreased IL-4 expression, while mRNA for mature IL-4 was concomitantly down-regulated. Importantly, only the simultaneous combination of apoptosis and necroptosis inhibitors prevented IL-4δ 13 expression and completely abrogated VPA-induced global histone H3K9 acetylation mark. Further, our work reveals a novel involvement of transcription factor c-Jun in the signaling network of IL-4, HDAC1, caspase-3 and mixed lineage kinase domain-like protein (MLKL). This study provides novel insights into the effects of epigenetic modulator VPA on human γδ T-cell differentiation.