Regulation of interleukin-1 beta secretion from macrophages via modulation of potassium ion (K+) channel activity

Abstract

A causal relationship exists between macrophage cholesterol levels and inflammation, for example, Interleukin-1β (IL-1β) secretion. A decrease in intracellular K+ is essential for inflammasome activation/IL-1β secretion and, herein, we examined the hypothesis that cellular cholesterol affects K+-channel activity and K+-efflux using mouse peritoneal macrophages (MPMs) and human/THP1 macrophages. An increase in cellular cholesterol led to a significant increase in K+ currents (> 350% in both MPM and THP1). Enhancing cholesterol efflux returned K+ currents back to basal levels with corresponding increase in intracellular K+ (11.2–14.5%) and reduced IL-1β secretion (32–62%). These data demonstrate a novel mechanism by which cellular cholesterol modulates inflammation/inflammasome via regulation of K+-channel activity and intracellular K+ levels. Attenuation of IL-1β secretion by Nateglinide/Repaglinide further suggests involvement of Kir6 channels.