Heme oxygenase-1 is an antifibrogenic protein in human hepatic myofibroblasts.
OBJECTIVE
Hepatic myofibroblasts play a key role in the development of liver fibrosis associated with chronic liver diseases. We have shown that oxidative stress is a messenger of 15-deoxy-delta-12,14-prostaglandin J2 (15-d-PGJ2) in human hepatic myofibroblasts. The aim of the present study was to investigate the role of a stress-inducible protein, heme oxygenase-1 (HO-1), in the action of 15-d-PGJ2.


METHODS
Expression of HO-1 was characterized in biopsy specimens of normal human liver and active cirrhosis by immunohistochemistry, and in cultured human hepatic myofibroblasts by Northern and Western blot analysis. Functional studies also were performed in cultured human hepatic myofibroblasts.


RESULTS
Immunohistochemistry showed that in biopsy specimens from normal livers, HO-1 protein expression was restricted to Kupffer cells. Biopsy specimens from cirrhotic patients displayed HO-1 protein both in macrophages and in myofibroblasts within fibrotic septa. HO-1 messenger RNA (mRNA) and protein also were detected in cultured human hepatic myofibroblasts and increased in response to 15-d-PGJ2 in a time- and dose-dependent manner. Induction of HO-1 in human hepatic myofibroblasts mediated 2 major antifibrogenic properties of 15-d-PGJ2, namely, inhibition of proliferation and of procollagen I mRNA expression. These effects were ascribed to bilirubin, one of the products of HO-1-mediated heme degradation.


CONCLUSIONS
This study shows that HO-1 is expressed in human hepatic myofibroblasts and induced during chronic liver injury. Moreover, these data unravel HO-1 as a major antifibrogenic pathway.
Li
Liying
L
Unité INSERM 581, Hôpital Henri Mondor, Créteil, France.
Grenard
Pascale
P
Nhieu
Jeanne Tran Van
JT
Julien
Boris
B
Mallat
Ariane
A
Habib
Ada
A
Lotersztajn
Sophie
S
D000328:Adult; D000368:Aged; D002455:Cell Division; D024042:Collagen Type I / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000201:enzymology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D024042:Collagen Type I; D008565:Membrane Proteins; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D015230:Prostaglandin D2