PMID- 19385008
OWN - NLM
STAT- MEDLINE
DCOM- 20090501
LR  - 20190701
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 84
IP  - 15-16
DP  - 2009 Apr 10
TI  - Accelerative effect of leflunomide on recovery from hepatic fibrosis involves 
      TRAIL-mediated hepatic stellate cell apoptosis.
PG  - 552-7
AB  - AIMS: Hepatic fibrosis is reversible, associated with apoptosis of activated 
      hepatic stellate cells (HSCs) as injury subsides, thus providing potential 
      targets for therapy. Little is known, however, about the course of this 
      condition. The objective of this study was to elucidate the mechanism by which 
      Kupffer cells regulate HSC biology during regression of hepatic fibrosis and the 
      effect of leflunomide on this process. MAIN METHODS: We harvested Kupffer cells 
      from rats during spontaneous recovery from liver fibrosis induced by carbon 
      tetrachloride (CCl4) and prepared recovery Kupffer cell conditioned medium 
      (KCCM). Culture-activated HSCs were pretreated in the absence or presence of 
      A771726, the active metabolite of leflunomide, and then stimulated with recovery 
      KCCM. KEY FINDINGS: Following stimulation with recovery KCCM, HSCs showed a 
      decrease in proliferation and an increase in apoptosis by a caspase-dependent 
      mechanism. Furthermore, pretreatment with A771726 markedly enhanced these 
      effects. Real-time quantitative PCR (Q-PCR) analysis showed increased expression 
      of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in Kupffer 
      cells during the spontaneous recovery phase. The pro-apoptotic function of KCCM 
      prepared from TRAIL siRNA-treated Kupffer cells was obviously decreased, 
      suggesting that TRAIL played an important role in recovery from hepatic fibrosis. 
      Moreover, A771726 enhanced recovery KCCM-induced apoptosis of HSCs by a mechanism 
      involving the inhibition of nuclear factor-kappa B (NF-kappaB) activation. 
      SIGNIFICANCE: Our results showed the role of TRAIL in the apoptosis of activated 
      HSCs that is induced by Kupffer cells prepared from livers recovering from 
      CCI4-induced fibrosis and provided insights into the resolution of fibrosis and 
      the mechanisms by which leflunomide might act upon liver fibrosis.
FAU - Tang, Xiaoming
AU  - Tang X
AD  - School of Pharmacy, Anhui Medical University, Hefei, Anhui Province 230032, 
      China.
FAU - Yang, Juntao
AU  - Yang J
FAU - Li, Jun
AU  - Li J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Isoxazoles)
RN  - 0 (NF-kappa B)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Tnfsf10 protein, rat)
RN  - G162GK9U4W (Leflunomide)
SB  - IM
MH  - Adjuvants, Immunologic/administration & dosage/pharmacology/*therapeutic use
MH  - Animals
MH  - Apoptosis/*drug effects/immunology
MH  - Blotting, Western
MH  - Cell Proliferation/drug effects
MH  - Culture Media, Conditioned
MH  - Hepatic Stellate Cells/*drug effects/immunology/metabolism/pathology
MH  - Isoxazoles/administration & dosage/pharmacology/*therapeutic use
MH  - *Kupffer Cells/cytology
MH  - Leflunomide
MH  - Liver Cirrhosis, Experimental/*drug therapy/immunology/metabolism/pathology
MH  - Male
MH  - NF-kappa B/antagonists & inhibitors
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - TNF-Related Apoptosis-Inducing Ligand/*biosynthesis
EDAT- 2009/04/23 09:00
MHDA- 2009/05/02 09:00
CRDT- 2009/04/23 09:00
PHST- 2009/04/23 09:00 [entrez]
PHST- 2009/04/23 09:00 [pubmed]
PHST- 2009/05/02 09:00 [medline]
AID - S0024-3205(09)00048-4 [pii]
AID - 10.1016/j.lfs.2009.01.017 [doi]
PST - ppublish
SO  - Life Sci. 2009 Apr 10;84(15-16):552-7. doi: 10.1016/j.lfs.2009.01.017.