title: Activation of TNF-alpha transcription utilizes distinct MAP kinase pathways in different macrophage populations.
abstract: Stimulation of macrophages by lipopolysaccharide (LPS) leads to the rapid activation of MAP kinases (MAPK) and the subsequent induction of cytokine gene 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-regulated kinase (ERK) pathway, blocked LPS-induced activation of tumor necrosis factor alpha (TNF-alpha) gene expression in a murine cell line derived from alveolar macrophages but not in a nonpulmonary macrophage cell line. These findings were confirmed using primary murine alveolar and peritoneal macrophages. 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 not mediated by NF-KB, LITAF, Egr-1, CREB, or ATF2/ c-Jun. Together, these studies demonstrate that transcriptional activation of the TNF-alpha gene requires the ERK signaling cascade in selected macrophage populations.
authors.affiliation: Department of Pathology, Boston University School of Medicine, Massachusetts, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Means
authors.forename: R P
authors.initials: RP
authors.lastname: Pavlovich
authors.forename: D
authors.initials: D
authors.lastname: Roca
authors.forename: M W
authors.initials: MW
authors.lastname: Vermeulen
authors.forename: M J
authors.initials: MJ
authors.lastname: Fenton
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012315:RNA Caps; D012333:RNA, Messenger / Q000096:biosynthesis; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017874:Immediate-Early Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D012315:RNA Caps; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one