High fatty acids modulate P2X7 expression and IL-6 release via the p38 MAPK pathway in PC12 cells

Abstract Diabetic neuropathy (DNP) is the most common chronic complication of diabetes. Elevated free fatty acids (FFAs) have been recently recognized as a major cause of nervous system damage in diabetes. P2X receptors play a primary role in regulation of neuronal interleukin (IL)-6 release, which is of paramount relevance to the functional changes of nerve system. The present study aimed to investigate the effects of high FFAs on the P2X 7 expression and IL-6 release in PC12 cells. High FFAs induced P2X 7 expression and IL-6 release significantly in PC12 cells. Moreover, high FFAs enhanced ATP or BzATP-induced Ca 2+ signals in PC12 cells. Inhibition of P2X 7 by transfection with P2X 7 -siRNA or co-culture with BBG (a specific P2X 7 inhibitor) at high concentrations of FFAs decreased ATP or BzATP-promoted Ca 2+ signals and IL-6 release in PC12 cells. High FFAs induced the phosphorylation of p38 in PC12 cells. Blockade of p38 pathways by SB-203580 inhibited P2X 7 up-expression, ATP or BzATP-evoked [Ca 2+ ] i rises as well as IL-6 release in PC12 cells exposed to high FFAs. Therefore, high concentrations of FFAs increased the expression of P2X 7 in PC12 cells via activation of p38 mitogen-activated protein kinase (MAPK) signaling pathway, which contributed to P2X 7 -mediated IL-6 release from PC12 cells.