Abstract
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiopathogenesis characterized by fibrous cholangiopathy of large and small bile ducts. Systemic administration of a murine TNF-related apoptosis-inducing ligand (TRAIL) receptor agonist induces a sclerosing cholangitis injury in C57BL/6 mice, suggesting endogenous TRAIL may contribute to sclerosing cholangitis syndromes. Cellular inhibitor of apoptosis proteins (cIAP-1 and cIAP-2) are negative regulators of inflammation and TRAIL receptor signaling. We hypothesized that if endogenous TRAIL promotes sclerosing cholangitis, then cIAP depletion should also induce this biliary tract injury. Herein, we show that cIAP protein levels are reduced in the interlobular bile ducts of human PSC livers. Downregulation of cIAPs in normal human cholangiocytes in vitro by use of a SMAC mimetic (SM) induces moderate, ripoptosome-mediated apoptosis and RIP1-independent upregulation of proinflammatory cytokines and chemokines. Cytokine and chemokine expression was mediated by the non-canonical activation of NF-κB. To investigate whether downregulation of cIAPs is linked to generation of a PSC-like phenotype, an SM was directly instilled into the mouse biliary tree. Twelve hours after biliary instillation, TUNEL-positive cholangiocytes were identified; 5 days later, PSC-like changes were observed in the SM-treated mice, including a fibrous cholangiopathy of the interlobular bile ducts, portal inflammation, significant elevation of serum markers of cholestasis and cholangiographic evidence of intrahepatic biliary tract injury. In contrast, TRAIL and TRAIL-receptor deficient mice showed no sign of cholangiopathy following SM intrabiliary injection. We conclude that in vivo antagonism of cIAPs in mouse biliary epithelial cells is sufficient to trigger cholangiocytes apoptosis and a proinflammatory response resulting in a fibrous cholangiopathy resembling human sclerosing cholangitis. Therefore, downregulation of cIAPs in PSC cholangiocytes may contribute to the development of the disease. Our results also indicate that inhibition of TRAIL signaling pathways may be beneficial in the treatment of PSC.
| Original language | English (US) |
|---|---|
| Article number | e2535 |
| Journal | Cell Death and Disease |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 5 2017 |
Bibliographical note
Funding Information:The authors thank Wafik El-Deiry for providing the Dr5-/- mice, Bing Huang for technical assistance with electron microscopy, Bruce Knudsen for technical assistance with cholangiography and Courtney Hoover for excellent secretarial assistance. This work was supported by NIH grants DK63947 (to GJG) and P30DK084567 (to the optical microscopy core of the Mayo Clinic Center for Cell Signaling in Gastroenterology), the Chris M. Carlos and Catharine N. Jockisch Carlos Foundation for PSC, the PSC Partners Seeking a Cure Foundation (to MEG), the American Liver Foundation (to PH) and the Mayo Foundation.
Publisher Copyright:
© The Author(s) 2017.
