Previously, the expression of a non-secreted IL-4 variant (IL-4delta13) 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-4delta13 expression in human gammadelta T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4delta13 was associated with increased cytoplasmic IL-4Ralpha 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-4delta13 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 gammadelta T-cell differentiation.
- Bhat, J.
- Sosna, J.
- Fritsch, J.
- Quabius, E. S.
- Schutze, S.
- Zeissig, S.
- Ammerpohl, O.
- Adam, D.
- Kabelitz, D.
Keywords
- HDAC inhibitors
- Il-4
- Immune response
- Immunity
- Immunology and Microbiology Section
- apoptosis
- necroptosis
- valproic acid
