Silica-induced TNF-alpha and TGF-beta1 expression in RAW264.7 cells are dependent on Src-ERK/AP-1 pathways

Abstract

The cytokines secreted by lung macrophages have been shown to play a critical role in the pathogenesis of silicosis, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) are prominent cytokines in silicosis, but the underlying mechanism remains to be determined. The aim of the present study was to investigate the roles of Src-mitogen-activated protein kinase (MAPKs)/activator protein-1 (AP-1) signaling pathways in silica-induced TNF-alpha and TGF-beta1 expression in macrophage cells (RAW264.7). It was found that silica activated Src, p38 kinase, and extracellular signal-regulated kinase (ERK) in RAW264.7 cells. The induction of TNF-alpha and TGF-beta1 by silica was suppressed by Src inhibitor (PP1), ERK inhibitor (PD98059), but not by p38 kinase inhibitor (SB203580). Dominant negative mutant c-Jun (TAM67) inhibited silica-induced AP-1 DNA binding activity and downregulated the TNF-alpha and TGF-beta1 expression. In addition, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by silica. Based on these findings, it was conclude that Src-ERK/AP-1 signaling pathways are involved in the TNF-alpha and TGF-beta1 expression induced by silica in macrophages.