Anti-hypoxic effect of interleukin-10 in hippocampal neurons is mediated by modulation of TASK-1 and TASK-3 channels activity

Abstract

It has been shown that anti-inflammatory cytokine interleukin-10 (IL-10) can exert anti-hypoxic effect preventing post-hypoxic neuronal hyperexcitability. Yet, exact mechanisms of IL-10 mediated anti-hypoxic action on neuronal function are not fully understood. We suggested that IL-10 can exert its anti-hypoxic action via modulation of activity of two-pore potassium TASK-1 and TASK-3 channels. To study the involvement of TASK-1 and TASK-3 channels we employed a combination of whole-cell patch clamp and pharmacological inhibitory analysis to assess if IL-10 and brief hypoxic episode can modulate K⁺ background leak current (I_leak) and membrane input resistance (R_in) in cultured hippocampal neurons. We found that IL-10 in a dose-dependent manner can significantly increase I_leak with concomitant reduction in R_in. Neurons that were exposed to brief hypoxic episode on contrary showed significant decrease in I_leak with concomitant increase in R_in. Pretreatment with IL-10 prior hypoxic episode was able to abolish negative effect of hypoxia on I_leak and R_in. IL-10 potentiating action on I_leak and R_in was occluded by co-addition of selective blockers of TASK-1 and TASK-3 channels - ML365 and PK-THPP. Co-addition of LY294002, an inhibitor of PI3-kinase occluded IL-10 action on I_leak and R_in showing involvement of PI3K-associated pathway in IL-10 mediated regulation of TASK channel function. Our results provide new insights into IL-10 mediated neuroprotective and anti-hypoxic actions showing TASK-1 and TASK-3 channels as downstream targets of this anti-inflammatory cytokine.

Keywords: Cultured hippocampal neurons; Hypoxic episode; Interleukin-10; Membrane input resistance; Potassium background leak current; TASK-1 and TASK-3 channels.