TY - JOUR T1 - Inhibition of Interleukin 10 Transcription through the SMAD2/3 Signaling Pathway by Ca<sup>2+</sup>-Activated K<sup>+</sup> Channel K<sub>Ca</sub>3.1 Activation in Human T-Cell Lymphoma HuT-78 Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 294 LP - 302 DO - 10.1124/mol.118.114405 VL - 95 IS - 3 AU - Miki Matsui AU - Junko Kajikuri AU - Hiroaki Kito AU - Kyoko Endo AU - Yuki Hasegawa AU - Shinya Murate AU - Susumu Ohya Y1 - 2019/03/01 UR - http://molpharm.aspetjournals.org/content/95/3/294.abstract N2 - The hyperpolarization induced by intermediate-conductance Ca2+-activated K+ channel (KCa3.1) activation increases the driving force for Ca2+ influx, which generally promotes cell proliferation, migration, and cytokine production in immunocompetent cells. Interleukin-10 (IL-10) from tumor-infiltrating lymphocytes and macrophages, lymphoma, and carcinoma cells facilitates escape from cancer immune surveillance; however, the role of KCa3.1 in IL-10 production remains unclear. The objective of the present study was to elucidate the involvement of KCa3.1 in IL-10 expression and production using the human T-cell lymphoma HuT-78 cells. In HuT-78 cells, IL-10 gene expression and production were reduced by treatment with the KCa3.1 activator, as 6-hour Western blotting showed that the protein expression ratio of phosphorylated Smad2 (P-Smad2)/Smad2, but not P-Smad3/Smad3, was decreased by the treatment with KCa3.1 activator in HuT-78 cells. Concomitant with this, the nuclear translocation of P-Smad2 was inhibited by KCa3.1 activator. Furthermore, the KCa3.1 activator–induced transcriptional repression of IL-10 disappeared with pretreatment with the calmodulin kinase II (CaMKII) inhibitor KN-62 for 1 hour, and KCa3.1 activator–induced decreases in the nuclear translocation of P-Smad2 were also prevented by pretreatment with KN-62. Taken together, the KCa3.1 activator–induced transcriptional repression of IL-10 is due to the inhibition of the nuclear translocation of P-Smad2 in HuT-78 cells, resulting in the prevention of P-Smad2/3 complex formation in nuclei, and the activation of CaMKII induced by KCa3.1 activators suppresses the constitutive activation of P-Smad2/3 in HuT-78 cells. Therefore, KCa3.1 activators have potential as a therapeutic option to suppress the tumor-promoting activities of IL-10. ER -