Silica-induced TNF-alpha and TGF-beta1 expression in RAW264.7 cells are dependent on Src-ERK/AP-1 pathways.
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.
Department of Pathology, Xiangya Medical School, Central South University, Changsha 410013, PR China.
Xiang
X
Li
Yongbin
Y
Hu
Zhongyuan
Z
Jin
Haiying
H
Jiang
Jifang
J
Wen
D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics; D010766:Phosphorylation; D010957:Plasmids; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000633:toxicity*; D012829:Silicosis / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology
D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases