title: Tumor necrosis factor alpha inhibits collagen alpha 1(I) gene expression in rat hepatic stellate cells through a G protein.
abstract: OBJECTIVE
  Tumor necrosis factor alpha (TNF-alpha) inhibits collagen gene expression in cultured fibroblasts. By binding to cell surface receptors, TNF-alpha promotes signals within the cells. The purpose of this study was to investigate the role played by G proteins in TNF-alpha-induced inhibition of collagen gene expression.
  
  
  METHODS
  Effect of TNF-alpha on collagen alpha 1(I) messenger RNA (mRNA) level was measured in cultured hepatic stellate cells in basal condition and after inhibiting or activating G proteins or the major intracellular signal transduction pathways.
  
  
  RESULTS
  TNF-alpha significantly decreased the level of alpha 1(I) collagen mRNA. Treatment of cells with pertussis toxin inhibited this effect, whereas blocking adenylate cyclase or protein kinase A had no effect. Likewise, blocking phospholipase A2, phospholipase C1 calcium channels, calmodulin, or protein kinase C did not eliminate the inhibitory effect of TNF-alpha on collagen mRNA. On the other hand, C2-ceramide and sphingomyelinase reproduced the effect of TNF-alpha on collagen gene expression, and TNF-alpha did not increase the effect of sphingomyelinase.
  
  
  CONCLUSIONS
  TNF-alpha-induced inhibition of alpha 1(I) collagen gene expression in a hepatic stellate cell line may be mediated by a pertussis toxin-sensitive G protein. TNF-alpha may inhibit this gene by using sphingomyelin/ceramide as an intracellular signal transduction pathway.
authors.affiliation: Servicio de Gastroenterologia, Hospital Universitario Doce de Octubre, Universidad Complutense, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Hernández-Muñoz
authors.forename: P
authors.initials: P
authors.lastname: de la Torre
authors.forename: J A
authors.initials: JA
authors.lastname: Sánchez-Alcázar
authors.forename: I
authors.initials: I
authors.lastname: García
authors.forename: E
authors.initials: E
authors.lastname: Santiago
authors.forename: M T
authors.initials: MT
authors.lastname: Muñoz-Yagüe
authors.forename: J A
authors.initials: JA
authors.lastname: Solís-Herruzo
mesh_terms: D037361:Adenylate Cyclase Toxin; D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D007295:Inositol Phosphates / Q000032:analysis / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D009355:Neomycin / Q000494:pharmacology; D037342:Pertussis Toxin; D010741:Phospholipases A / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D054467:Phospholipases A2; D011347:Procollagen / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011493:Protein Kinase C / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D011796:Quinacrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D013109:Sphingomyelins / Q000032:analysis / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D002147:Calmodulin; D007295:Inositol Phosphates; D011347:Procollagen; D012333:RNA, Messenger; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D000001:Calcimycin; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D013108:Sphingomyelin Phosphodiesterase; D019204:GTP-Binding Proteins; D011796:Quinacrine; D019311:Staurosporine; D009355:Neomycin