TY - JOUR
T1 - Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis
AU - Taimr, Pavel
AU - Higuchi, Hajime
AU - Kocova, Eva
AU - Rippe, Richard A.
AU - Friedman, Scott
AU - Gores, Gregory J.
N1 - Funding Information:
Abbreviations: HSC, hepatic stellate cell; α-SMA, α–smooth muscle actin; NF- κB, nuclear factor κB; DR, death receptor; TRAIL, tumor necrosis factor–related apoptosis-inducing ligand; TRAIL-R, tumor necrosis factor–related apoptosis-inducing ligand receptor; DMEM, Dulbecco’s minimum essential medium; PCR, polymerase chain reaction; mRNA, messenger RNA; DcR, decoy receptor. From the 1Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, MN; 2Center for Gastrointestinal Disease and Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; and 3Division of Liver Disease, Mount Sinai School of Medicine, New York, NY. Received August 19, 2002; accepted September 30, 2002. Supported by grant DK41876 from the National Institutes of Health, as well as the Mayo Foundation. Address reprint requests to: Gregory J. Gores, M.D., Mayo Medical School, Clinic, and Foundation, 200 First St. SW, Rochester, MN 55905. E-mail: gores.gregory@mayo.edu; fax: 507-284-0762. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3701-0016$35.00/0 doi:10.1053/jhep.2003.50002
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Apoptosis has emerged as an important mechanism to reduce numbers of activated stellate cells during the resolution phase of hepatic fibrosis. These observations suggest that activated stellate cells may be more susceptible to apoptotic stimuli than their quiescent counterparts. Because other activated cell types are more sensitive than their quiescent phenotypes to apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we examined the expression of TRAIL death receptors (DRs) and susceptibility to TRAIL cytotoxicity in stellate cells undergoing progressive activation. A spontaneously immortalized human stellate cell line, LX-2, was analyzed during 14 days of progressive activation following plating, during which time α-smooth muscle actin (α-SMA) and a β-crystallin (markers of stellate cell activation) messenger RNA (mRNA) increased 7-fold and 5-fold, respectively. During this same interval, TRAIL-R1/DR4 and TRAIL-R2/DR5 mRNA expression increased 18-fold and 17.6-fold, although TRAIL-R2/DR5 expression was quantitatively 103-fold greater than TRAIL-R1/DR4; parallel changes occurred in TRAIL/DR5 protein expression and cellular susceptibility to TRAIL-mediated apoptosis. Similar findings were observed in primary murine stellate cells undergoing activation on a plastic surface. In conclusion, stellate cells show activation-dependent TRAIL-R2/DR5 expression and TRAIL-mediated apoptosis. Because TRAIL-R2/DR5 is not expressed by hepatocytes, TRAIL/DR5 agonists may be useful in reducing fibrosis by inducing stellate cell apoptosis.
AB - Apoptosis has emerged as an important mechanism to reduce numbers of activated stellate cells during the resolution phase of hepatic fibrosis. These observations suggest that activated stellate cells may be more susceptible to apoptotic stimuli than their quiescent counterparts. Because other activated cell types are more sensitive than their quiescent phenotypes to apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we examined the expression of TRAIL death receptors (DRs) and susceptibility to TRAIL cytotoxicity in stellate cells undergoing progressive activation. A spontaneously immortalized human stellate cell line, LX-2, was analyzed during 14 days of progressive activation following plating, during which time α-smooth muscle actin (α-SMA) and a β-crystallin (markers of stellate cell activation) messenger RNA (mRNA) increased 7-fold and 5-fold, respectively. During this same interval, TRAIL-R1/DR4 and TRAIL-R2/DR5 mRNA expression increased 18-fold and 17.6-fold, although TRAIL-R2/DR5 expression was quantitatively 103-fold greater than TRAIL-R1/DR4; parallel changes occurred in TRAIL/DR5 protein expression and cellular susceptibility to TRAIL-mediated apoptosis. Similar findings were observed in primary murine stellate cells undergoing activation on a plastic surface. In conclusion, stellate cells show activation-dependent TRAIL-R2/DR5 expression and TRAIL-mediated apoptosis. Because TRAIL-R2/DR5 is not expressed by hepatocytes, TRAIL/DR5 agonists may be useful in reducing fibrosis by inducing stellate cell apoptosis.
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U2 - 10.1053/jhep.2003.50002
DO - 10.1053/jhep.2003.50002
M3 - Article
C2 - 12500193
AN - SCOPUS:0037219276
SN - 0270-9139
VL - 37
SP - 87
EP - 95
JO - Hepatology
JF - Hepatology
IS - 1
ER -