title: Suppression of LPS-induced tumor necrosis factor-alpha gene expression by microtubule disrupting agents.
abstract: Microtubule disrupting agents such as colchicine have been shown to reduce TNF-alpha production in macrophages. To examine molecular mechanisms underlying the action of colchicine, TNF-alpha gene expression was studied in the murine macrophage cell line PU5-1.8. An LPS stimulation caused an intense up-regulation of TNF-alpha gene expression which was followed by a high TNF-alpha protein production. Simultaneous addition of colchicine (10 microM) suppressed LPS-induced TNF-alpha mRNA accumulation by one-third and TNF-alpha protein release by two-thirds. This effect was shared by vinblastine and vincristine, chemically different agents that also disrupt microtubule polymerization. For full suppressive activity on TNF-alpha gene expression, colchicine had to be present for 3 h in LPS-stimulated macrophage cultures. With nuclear run-on transcription experiments we could demonstrate that colchicine primarily inhibited de novo gene transcription and did not accelerate degradation of TNF-alpha mRNA in actinomycin D-treated macrophages. Thus, the well-known antiinflammatory action of microtubule depolymerizing agents may be largely due to a reduced TNF-alpha gene expression.
authors.affiliation: Institute of Immunology, Philipps University, Marburg, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: G S
authors.initials: GS
authors.lastname: Davis
authors.forename: C
authors.initials: C
authors.lastname: Mohr
authors.forename: M
authors.initials: M
authors.lastname: Nain
authors.forename: D
authors.initials: D
authors.lastname: Gemsa
mesh_terms: D000818:Animals; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics*; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014750:Vincristine; D014747:Vinblastine; D003078:Colchicine