Characterization of intracellular pathways leading to coinduction of thrombospondin-1 and TGF-beta1 expression in rat hepatic stellate cells.
Accumulating evidence has identified Thrombospondin (TSP)-1 as important activator of latent TGF-beta. Since little is known about signal transduction pathways regulating TSP expression in liver, we investigated cytokine-mediated upregulation of TSP-1 and TGF-beta1 in primary rat hepatic stellate cells (HSC). PDGF-BB and TNF-a rapidly coinduce mRNA levels of TSP-1 and TGF-beta1. Interestingly, blockade of basal Erk activity by synthetic Erk-binding peptides also leads to strong induction of both mRNA transcripts in non-stimulated cells. We show that PDGF-BB induces TSP-1 and TGF-beta1 via the src kinase pathway whereas TNF-a utilizes the MAPK/Erk pathway. However, especially TSP-1 induction by both cytokines involves a pathway, which depends to a certain extent on PI3 kinase activity. In summary the data illustrate specific pathways activated by PDGF-BB and TNF-a in HSC giving new insights into the tightly controlled mechanisms regulating TSP-1 and TGF-beta1 expression in these cells.
Breitkopf
Katja
K
Mol. Alcohol Research in Gastroenterology, Department of Medicine II, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. katja.breitkopf@med.ma.uni-heidelberg.de
Sawitza
Iris
I
Gressner
Axel M
AM
D000818:Animals; D000077214:Becaplermin; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D010455:Peptides; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000077214:Becaplermin; D012313:RNA; D019061:src-Family Kinases