Cholangiocyte senescence by way of N‐ras activation is a characteristic of primary sclerosing cholangitis

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...

Celý popis

Uložené v:
Podrobná bibliografia
Vydané v:Hepatology (Baltimore, Md.) Ročník 59; číslo 6; s. 2263 - 2275
Hlavní autori: Tabibian, James H., O'Hara, Steven P., Splinter, Patrick L., Trussoni, Christy E., LaRusso, Nicholas F.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Wolters Kluwer Health, Inc 01.06.2014
Predmet:
Adult
Bile
Bodily Secretions
Case-Control Studies
Cells, Cultured
Cellular Senescence
Cholangitis, Sclerosing - etiology
Cholangitis, Sclerosing - metabolism
Cholangitis, Sclerosing - physiopathology
Enzyme Activation
Genes, ras
Hepatology
Humans
Middle Aged
Phenotype
ras Proteins - antagonists & inhibitors
ras Proteins - metabolism
Rodents
Senescence
ISSN:0270-9139, 1527-3350, 1527-3350
On-line prístup:Získať plný text
Tagy: Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
Popis
Shrnutí: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)
Bibliografia: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).
These authors contributed equally to this work.
Potential conflict of interest: Nothing to report.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:0270-9139
1527-3350
1527-3350
DOI:10.1002/hep.26993