Tumor necrosis factor alpha inhibits collagen alpha 1(I) gene expression in rat hepatic stellate cells through a G protein

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 113; no. 2; p. 625
• Main Authors: Hernández-Muñoz, I, de la Torre, P, Sánchez-Alcázar, J A, García, I, Santiago, E, Muñoz-Yagüe, M T, Solís-Herruzo, J A
• Format: Journal Article
• Language: English
• Published: United States 01.08.1997
• Subjects: Adenylate Cyclase Toxin; Animals; Arachidonic Acids - analysis; Arachidonic Acids - metabolism; Calcimycin - pharmacology; Calcium Channel Blockers - pharmacology; Calmodulin - antagonists & inhibitors; Calmodulin - pharmacology; Cells, Cultured; Cholera Toxin - pharmacology; Cyclic AMP - analysis; Cyclic AMP - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; GTP-Binding Proteins - physiology; Inositol Phosphates - analysis; Inositol Phosphates - metabolism; Liver - chemistry; Liver - cytology; Liver - metabolism; Neomycin - pharmacology; Pertussis Toxin; Phospholipases A - analysis; Phospholipases A - antagonists & inhibitors; Phospholipases A - physiology; Phospholipases A2; Procollagen - analysis; Procollagen - genetics; Procollagen - metabolism; Protein Kinase C - analysis; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Quinacrine - pharmacology; Rats; RNA, Messenger - analysis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - physiology; Sphingomyelin Phosphodiesterase - pharmacology; Sphingomyelins - analysis; Sphingomyelins - metabolism; Staurosporine - pharmacology; Tumor Necrosis Factor-alpha - pharmacology; Virulence Factors, Bordetella - pharmacology
• ISSN: 0016-5085
• DOI: 10.1053/gast.1997.v113.pm9247485

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. 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. 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. 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.