These authors contributed equally to this work.
Autoimmune, Cholestatic and Biliary Disease
Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis
Article first published online: 25 APR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 6, pages 2263–2275, June 2014
How to Cite
Tabibian, J. H., O'Hara, S. P., Splinter, P. L., Trussoni, C. E. and LaRusso, N. F. (2014), Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis. Hepatology, 59: 2263–2275. doi: 10.1002/hep.26993
Potential conflict of interest: Nothing to report.
Supported by National Institutes of Health grants AI089713 (to S.P.O.), DK57993 (to N.F.L), the Mayo Foundation, PSC Partners Seeking a Cure, and the Clinical and Optical Microscopy Cores of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567).
- Issue published online: 28 MAY 2014
- Article first published online: 25 APR 2014
- Accepted manuscript online: 4 JAN 2014 07:17AM EST
- Manuscript Accepted: 25 DEC 2013
- Manuscript Received: 13 AUG 2013
Primary sclerosing cholangitis (PSC) is an incurable cholangiopathy of unknown etiopathogenesis. Here we tested the hypothesis that cholangiocyte senescence is a pathophysiologically important phenotype in PSC. We assessed markers of cellular senescence and senescence-associated secretory phenotype (SASP) in livers of patients with PSC, primary biliary cirrhosis, hepatitis C, and in normals by fluorescent in situ hybridization (FISH) and immunofluorescence microscopy (IFM). We tested whether endogenous and exogenous biliary constituents affect senescence and SASP in cultured human cholangiocytes. We determined in coculture whether senescent cholangiocytes induce senescence in bystander cholangiocytes. Finally, we explored signaling mechanisms involved in cholangiocyte senescence and SASP. In vivo, PSC cholangiocytes expressed significantly more senescence-associated p16INK4a and γH2A.x compared to the other three conditions; expression of profibroinflammatory SASP components (i.e., IL-6, IL-8, CCL2, PAI-1) was also highest in PSC cholangiocytes. In vitro, several biologically relevant endogenous (e.g., cholestane 3,5,6 oxysterol) and exogenous (e.g., lipopolysaccharide) molecules normally present in bile induced cholangiocyte senescence and SASP. Furthermore, experimentally induced senescent human cholangiocytes caused senescence in bystander cholangiocytes. N-Ras, a known inducer of senescence, was increased in PSC cholangiocytes and in experimentally induced senescent cultured cholangiocytes; inhibition of Ras abrogated experimentally induced senescence and SASP. Conclusion: Cholangiocyte senescence induced by biliary constituents by way of N-Ras activation is an important pathogenic mechanism in PSC. Pharmacologic inhibition of N-Ras with a resultant reduction in cholangiocyte senescence and SASP is a new therapeutic approach for PSC. (Hepatology 2014;59:2263–2275)