Silica-induced chemokine expression in alveolar type II cells is mediated by TNF-alpha

Recent evidence has suggested that epithelial cells may contribute to the i nflammatory response in the lung after exposure to crystalline silica throu gh the production of and response to specific growth factors, chemokines, a nd cytokines. However, the exact cellular and molecular responses of epithe lial cells to silica exposure remains unclear. Using a murine alveolar type II cell line [murine lung epithelial (MLE)-15 cell line], we measured the early changes in various cytokine and chemokine mRNA species after exposure of the cells to 4-35 mu g/cm(2) of silica (cristobalite), interferon (IFN) -gamma, tumor necrosis factor (TNF)-alpha, and lipopolysaccharide (LPS) alo ne or in combination. Total mRNA was isolated and assayed with an RNase pro tection assay after 6 and 24 h of exposure. Cristobalite exposure alone led to an increase in monocyte chemotactic protein (MCP)-1, macrophage inflamm atory protein (MIP)-2, and regulated on activation normal T cells expressed and secreted (RANTES) mRNAs. Treatment with IFN-gamma alone increased MCP- 1 mRNA levels. Treatment with TNF-alpha or LPS alone led to an increase in MCP-1 and MIP-2 mRNA. The combination of cristobalite plus TNF-alpha led to an additive increase in MCP-1 and MIP-2, whereas cristobalite plus IFN-gam ma or LPS had a synergistic effect. We also found with a TNF-alpha-neutrali zing antibody that TNF-alpha plays a major role in mediating the type II ce ll chemokine response to cristobalite exposure. The results indicate that t he cristobalite-induced chemokine response in the lung epithelium is mediat ed in part by TNF-alpha and can be enhanced by macrophage- and lymphocyte-d erived inflammatory mediators in an additive and synergistic fashion.