Activation of TNF-alpha transcription utilizes distinct MAP kinase pathways in different macrophage populations

Stimulation of macrophages by lipopolysaccharide (LPS) leads to the rapid a ctivation of MAP kinases (MAPK) and the subsequent induction of cytokine ge ne expression. We sought to determine whether LPS-inducible cytokine genes were differentially regulated in macrophages derived from different tissues . Our studies revealed that PD98059, an inhibitor of the extracellular-regu lated kinase (ERK) pathway, blocked LPS-induced activation of tumor necrosi s factor alpha (TNF-alpha) gene expression in a murine cell line derived fr om alveolar macrophages but not in a nonpulmonary macrophage cell line. The se findings were confirmed using primary murine alveolar and peritoneal mac rophages, This suggests that the TNF-alpha promoter contains MAPK-dependent and -independent regulatory elements that are used in a cell type-specific manner. We also found that differences in MAPK-regulated signaling were no t mediated by NF-kappa B, LITAF, Egr-1, CREB, or ATF2/c-Jun, Together, thes e studies demonstrate that transcriptional activation of the TNF-alpha gene requires the ERK signaling cascade in selected macrophage populations.