The Ca2+-activated K+ channel (KCa3.1) is one of key molecules that control Ca2+ entry, and the increase of Ca2+ influx generally promotes cell proliferation, migration, and cytokine production in immune cells. The anti-inflammatory cytokine, interleukin-10 (IL-10) plays a crucial role in escape from tumor immune surveillance. Recently, we discovered the dysregulated IL-10 expression and production in human T-cell lymphoma HuT-78 cells. We also showed the involvement of Smad2/3 signaling pathway in this. Both Smad2 and Smad3 were constantly activated (phosphorylated) in HuT-78 cells, Phospho-Smad2 (P-Smad2) protein expression and nuclear translocation of P-Smad2 were inhibited by the KCa3.1 activators. Pre-treatment with a calmodulin kinase II inhibitor, KN-62 suppressed the KCa3.1 activator-induced IL-10 down-regulation and the nuclear translocation of P-Smad2. These results suggest that the KCa3.1 activator-induced transcriptional repression of IL-10 in HuT-78 cells is due to the inhibition of the nuclear translocation of P-Smad2 and KCa3.1 activators have potential as a therapeutic option to suppress the tumor-promoting activities of IL-10 through CaMKII signaling.

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