title: 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.
abstract: Previously, the expression of a non-secreted IL-4 variant (IL-4δ13) 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-4δ13 expression in human γδ T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4δ13 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-4δ13 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.
authors.affiliation: Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Jaydeep
authors.initials: J
authors.lastname: Bhat
authors.affiliation: Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.|Current address: Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, USA.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sosna
authors.affiliation: Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Fritsch
authors.affiliation: Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.|Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Elgar Susanne
authors.initials: ES
authors.lastname: Quabius
authors.affiliation: Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
authors.affiliation: Department of Internal Medicine I, Christian-Albrechts-University, Kiel, Germany.|Current address: Department of Medicine I, University Medical Center Dresden, Technical University Dresden, Dresden, Germany.|Current address: Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, Dresden, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
authors.affiliation: Institute of Human Genetics, University Medical Center Schleswig-Holstein Kiel, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.affiliation: Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
authors.affiliation: Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
mesh_terms: D000375:Aging / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D009154:Mutation / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D015854:Up-Regulation; D014635:Valproic Acid / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015847:Interleukin-4; D014635:Valproic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: HDAC inhibitors; IL-4; Immune response; Immunity; Immunology and Microbiology Section; apoptosis; necroptosis; valproic acid