Aberrant expression of redox regulatory proteins in patients with concomitant primary Sclerosing cholangitis/inflammatory bowel disease.

Objective: Primary Sclerosing Cholangitis (PSC) is a severe cholestatic liver disease characterized by progressive peri-biliary tract inflammation, elevated oxidative stress and hepatocellular injury. A hallmark of PSC patients is the concurrent diagnosis of Inflammatory Bowel Disease occurring in approximately 70%-80% of PSC patients (PSC/IBD). We previously reported dysregulation of key anti-oxidant pathways in PSC/IBD. The objective of this study was to expand previous data by examining the abundance of thioredoxins (Trx) in PSC/IBD.

Methods: Using hepatic tissue and whole cell extracts isolated from age-matched healthy humans and patients diagnosed with end stage PSC/IBD, the protein abundance of thioredoxin, thioredoxin reductase (TrxR1), and their downstream substrates peroxiredoxins was assessed.

Results: Western blot analyses of thioredoxin and peroxiredoxin abundance revealed significant increases in abundance of Trx1 and TrxR1 whereas expression of thioredoxin-interacting protein was significantly decreased in PSC/IBD. Concurrently, abundance of cytosolic peroxiredoxins was not significantly impacted. The abundance of mitochondrial Trx2, along with peroxiredoxins 3, 5 and 6 were significantly decreased by concurrent PSC/IBD. Histological staining of Trx1/TrxR1 revealed elevated nuclear Trx1 and TrxR1 staining within cholangiocytes as well as an overall periportal increase in expression in PSC/IBD. An examination of additional anti-oxidant responses reveal suppression of gamma-glutamylcysteine synthetase and heme oxygenase (HO-1) whereas expression of the protein chaperone glucose regulated protein 78 increased suggesting elevated cellular stress in PSC/IBD.

Conclusions: Results herein suggest that in addition to severe dysregulation of anti-oxidant responses, cholestasis impacts both cytosolic/nuclear (Trx1) as well as mitochondrial (Trx2) redox signaling and control pathways.