An NO derivative of ursodeoxycholic acid protects against Fas-mediated liver injury by inhibiting caspase activity.
Caspases are key mediators in liver inflammation and apoptosis. In the present study we provide evidence that a nitric oxide (NO) derivative of ursodeoxycholic acid (UDCA), NCX-1000 ([2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester]), protects against liver damage in murine models of autoimmune hepatitis induced by i.v. injection of Con A or a Fas agonistic antibody, Jo2. Con A administration causes CD4(+) T lymphocytes to accumulate in the liver and up-regulates FasL expression, resulting in FasL-mediated cytotoxicity. Cotreating mice with NCX-1000, but not with UDCA, protected against liver damage induced by Con A and Jo2, inhibited IL-1beta, IL-18, and IFN-gamma release and caspase 3, 8, and 9 activation. Studies on HepG2 cells demonstrated that NCX-1000, but not UDCA, directly prevented multiple caspase activation induced by Jo2. Incubating HepG2 cells with NCX-1000 resulted in intracellular NO formation and a DTT-reversible inhibition of proapoptotic caspases, suggesting that cysteine S-nitrosylation was the main mechanism responsible for caspase inhibition. Collectively, these data suggest that NCX-1000 protects against T helper 1-mediated liver injury by inhibiting both the proapoptotic and the proinflammatory branches of the caspase superfamily.
Fiorucci
S
S
Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, 06122 Perugia, Italy. fiorucci@unipg.it
Mencarelli
A
A
Palazzetti
B
B
Del Soldato
P
P
Morelli
A
A
Ignarro
L J
LJ
D000818:Animals; D001483:Base Sequence; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers; D015536:Down-Regulation; D053222:Fas Ligand Protein; D019693:Hepatitis, Autoimmune / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008562:Membrane Glycoproteins / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009566:Nitrates; D012333:RNA, Messenger / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives
C433771:2-methyl-3-(2-((4-nitrooxybutyloxy)carbonyl)vinyl)phenyl ursodeoxycholic acid ester; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D009566:Nitrates; D012333:RNA, Messenger; D012459:Salicylates; D014580:Ursodeoxycholic Acid