Molecular mechanisms regulating the antifibrogenic protein heme-oxygenase-1 in human hepatic myofibroblasts.
OBJECTIVE
Hepatic myofibroblasts are central in liver fibrogenesis associated with chronic liver diseases. We previously showed that heme-oxygenase-1 (HO-1) displays antifibrogenic properties in human hepatic myofibroblasts. Here, we further investigated the mechanisms regulating HO-1 expression.


METHODS
Expression of HO-1 was assayed in cultured human hepatic myofibroblasts by Northern and Western blot. Functional studies were also performed in cultured human hepatic myofibroblasts.


RESULTS
15-Deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) elicited inhibition of proliferation and of alpha1(I) collagen mRNA expression. These effects were reproduced by the glutathione depletor diethyl maleate and blunted by the glutathione precursor N-acetyl cysteine, indicating the involvement of oxidative stress. Two consecutive events mediated inhibition of proliferation and of alpha1(I) collagen mRNA expression by 15-d-PGJ2: (i) mild oxidative stress characterized by a transient GSH decrease and (ii) activation of p38 MAPK, resulting in increased HO-1 mRNA stability.


CONCLUSIONS
Our results provide new insights into the regulatory mechanisms governing HO-1 expression in human hepatic myofibroblasts and identify mild oxidative stress and p38 MAPK as two consecutive early signals promoting HO-1 induction that are crucial for its antifibrogenic properties, namely inhibition of growth and extracellular matrix gene expression.
Li
Liying
L
Unité INSERM 581, Hôpital Henri Mondor, 94010 Créteil, France.
Julien
Boris
B
Grenard
Pascale
P
Teixeira-Clerc
Fatima
F
Mallat
Ariane
A
Lotersztajn
Sophie
S
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D024042:Collagen Type I; D008565:Membrane Proteins; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2