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

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 Ca2+ 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 Ca2+ 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 [Ca2+](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. (C) 2013 Elsevier Inc. All rights reserved.