Extracellular acidification stimulates IL-6 production and Ca2+ mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells

Abstract

The asthmatic airway has been shown to be an acidic environment that may be involved in the pathophysiological features of asthma. However, the mechanism by which an acidic pH modulates the cellular activities involved in the asthmatic airway remains elusive. Here, we characterized acidic pH-induced actions in human airway smooth muscle cells (ASMCs). Extracellular acidification stimulates the mRNA expression and protein production of IL-6, a proinflammatory cytokine, in association with the phosphorylation of extracellular signal-regulated kinase (ERK) and p38MAPK, reflecting the activation of the enzymes. Acidification-induced cytokine production was inhibited by inhibitors of ERK and p38MAPK. Acidification also increased intracellular Ca2+ concentration, which was accompanied by cell rounding, most likely reflecting contraction. In ASMCs, OGR1 is expressed at by far the highest levels among proton-sensing G protein-coupled receptors. The knockdown of OGR1 and Gq/11 protein with their specific small interfering RNAs and an inhibition of Gq/11 protein with YM-254890 attenuated the acidification-induced actions. We conclude that extracellular acidification stimulates IL-6 production and Ca2+ mobilization through proton-sensing OGR1 receptors/Gq/11 proteins in human ASMCs.