Increased susceptibility of cholangiocytes to tumor necrosis factor-alpha cytotoxicity after bile duct ligation.
Tumor necrosis factor (TNF)-alpha plays a critical role in epithelial cell injury. However, the role of TNF-alpha in mediating cholangiocyte injury under physiological or pathophysiological conditions is unknown. Thus we assessed the effects of TNF-alpha alone or following sensitization by actinomycin D on cell apoptosis, proliferation, and basal and secretin-stimulated ductal secretion in cholangiocytes from normal or bile duct-ligated (BDL) rats. Cholangiocytes from normal or BDL rats were highly resistant to TNF-alpha alone. However, presensitization by actinomycin D increased apoptosis in cholangiocytes following BDL and was associated with an inhibition of proliferation and secretin-stimulated ductal secretion. Thus TNF-alpha mediates cholangiocyte injury and altered ductal secretion following bile duct ligation. These observations suggest that cholestasis may enhance susceptibility to cytokine-mediated cholangiocyte injury.
Alpini
Gianfranco
G
Department of Internal Medicine, Texas A&M University System Health Science Center, College of Medicine, Temple, TX 76502, USA.
Ueno
Yoshiyuki
Y
Tadlock
Laura
L
Glaser
Shannon S
SS
LeSage
Gene
G
Francis
Heather
H
Taffetani
Silvia
S
Marzioni
Marco
M
Alvaro
Domenico
D
Patel
Tushar
T
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D001651:Cholestasis, Extrahepatic / Q000378:metabolism / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004347:Drug Interactions; D066298:In Vitro Techniques; D008026:Ligation; D008297:Male; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D000970:Antineoplastic Agents; D011500:Protein Synthesis Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D000242:Cyclic AMP