Leptin Increases TNF-alpha Expression and Production through Phospholipase D1 in Raw 264.7 Cells

Abstract

Epidemiological evidence suggests that obesity is associated with inflammation of the respiratory tract and the pathogenesis of asthma. The purpose of this study was to examine the role of phospholipase D1 (PLD1) in leptin-induced expression of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha, and to suggest a molecular link between obesity and respiratory tract inflammation. We investigated whether leptin, a typical adipocytokine, plays a role in the expression of TNF-alpha through increased PLD1 activity in Raw 264.7. Leptin enhanced the activity of PLD1 through activation of PLC gamma and Src, while PLD1 siRNA decreased the leptin-induced expression and production of TNF-alpha. Leptin-induced PLD activation was also inhibited by a PLCc inhibitor (PAO) and Src kinase inhibitor (PP2), indicating that PLCc and Src kinase are upstream activators of PLD1. Down-regulation of PLD1 also completely blocked activation of p70S6K, an activator of JNK. Leptin-induced expression of TNF-alpha was also prevented by inhibition of p70S6K and JNK. Taken together, these results indicate that PLD1 acts as an important regulator of leptin-induced expression of TNF-alpha by participating in the PLCc/Src/PLD1/PA/ p70S6K/JNK pathway.