Interleukin-17 Reduces βENaC via MAPK Signaling in Vascular Smooth Muscle Cells.

Abstract

Degenerin proteins, such as the beta epithelial Na+ channel (βENaC), are essential in the intracellular signaling of pressure-induced constriction, an important vascular smooth muscle cell (VSMC) function. While certain cytokines reduce ENaC protein in epithelial tissue, it is unknown if interleukin-17 (IL-17), a potent pro-inflammatory cytokine, directly mediates changes in membrane-associated βENaC in VSMCs. Therefore, we tested the hypothesis that exposure to IL-17 reduces βENaC in VSMCs through canonical mitogen-activated protein kinase (MAPK) signaling pathways. We treated cultured rat VSMCs (A10 cell line) with IL-17 (1–100 ng/mL) for 15 min to 16 h and measured expression of βENaC, p38MAPK, c-jun kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). IL-17 reduced βENaC protein expression in a concentration-dependent fashion and increased phosphorylation of p38MAPK by 15 min and JNK by 8 h. NFκB was unaffected by IL-17 in VSMCs. IL-17 treatment reduced VSMC viability but had no effect on cell death. To determine the underlying signaling pathway involved in this response, VSMCs were treated before and during IL-17 exposure with p38MAPK or JNK inhibitors. We found that JNK blockade prevented IL-17-mediated βENaC protein suppression. These data demonstrate that the pro-inflammatory cytokine IL-17 regulates VSMC βENaC via canonical MAPK signaling pathways, raising the possibility that βENaC-mediated loss of VSMC function may occur in inflammatory disorders.