Abstract
The up-regulated expression of the Ca2+-activated K+ channel KCa3.1 in inflammatory CD4+ T cells has been implicated in the pathogenesis of inflammatory bowel disease (IBD) through the enhanced production of inflammatory cytokines, such as interferon-γ (IFN-γ). However, the underlying mechanisms have not yet been elucidated. The objective of the present study is to clarify the involvement of histone deacetylases (HDACs) in the up-regulation of KCa3.1 in the CD4+ T cells of IBD model mice. The expression levels of KCa3.1 and its regulators, such as function-modifying molecules and transcription factors, were quantitated using a real-time polymerase chain reaction (PCR) assay, Western blotting, and depolarization responses, which were induced by the selective KCa3.1 blocker TRAM-34 (1 μM) and were measured using a voltage-sensitive fluorescent dye imaging system. The treatment with 1 μM vorinostat, a pan-HDAC inhibitor, for 24 h repressed the transcriptional expression of KCa3.1 in the splenic CD4+ T cells of IBD model mice. Accordingly, TRAM-34-induced depolarization responses were significantly reduced. HDAC2 and HDAC3 were significantly up-regulated in the CD4+ T cells of IBD model mice. The down-regulated expression of KCa3.1 was observed following treatments with the selective inhibitors of HDAC2 and HDAC3. The KCa3.1 K+ channel regulates inflammatory cytokine production in CD4+ T cells, mediating epigenetic modifications by HDAC2 and HDAC3.
Highlights
The intermediate-conductance Ca2+-activated K+ channel KCa3.1 controls Ca2+-dependent signaling pathways and plays crucial roles in proliferation, migration, apoptosis, and cytokine production in T cells [1,2,3,4]
We previously reported the involvement of histone deacetylases (HDACs) (HDAC2 and HDAC3) in KCa3.1 transcription in human breast cancer cells [21]
Among six KCa3.1 function-modifying molecules (NDPK-B, PI3KC2B, phosphatase 1 (PHPT1), MTMR6, tripartite motif containing-27 (TRIM-27), and phosphoglycerate mutase family member 5 (PGAM5)), the positive regulator of KCa3.1 activity, nucleoside diphosphate kinase-B (NDPK-B) was the most abundantly expressed in splenic CD4+CD25− T cells, and a significant increase was observed in its expression level (Figure 1B)
Summary
The intermediate-conductance Ca2+-activated K+ channel KCa3.1 controls Ca2+-dependent signaling pathways and plays crucial roles in proliferation, migration, apoptosis, and cytokine production in T cells [1,2,3,4]. Previous studies demonstrated the involvement of KCa3.1 in the pathogenesis of inflammatory bowel disease (IBD) [5,6,7,8]. Concomitant with these studies, a recent clinical study showed that the expression levels of KCa3.1 transcripts were higher in IBD patients than in controls [9]. Several transcriptional regulators of KCa3.1 have been identified in various cell types: activator protein-1 (AP-1) [15,16,17,18], repressor element silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) [19,20], and histone deacetylases [21]. We previously reported the involvement of HDACs (HDAC2 and HDAC3) in KCa3.1 transcription in human breast cancer cells [21]
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