The primary biliary epithelial cells of patients with primary sclerosing cholangitis (PSC) seem to be hyper-responsive to intestinal endotoxins. The resulting endotoxin intolerance could contribute to chronic cholangitis.
Healthy people are known to have an innate immune hyporesponsiveness to many intestinal endotoxins. By contrast, patients with prototypic chronic inflammatory cholangiopathies have an activated innate immune phenotype. The authors of a recent paper speculate that this dysregulation could lead to enhanced exposure to endotoxins and thus to the perpetuation of chronic inflammation. However, little work has been done to determine what underlies this response.
Increased expression of TLR and NOD proteins was found in ... patients with PSC...
The researchers analyzed the expression of the toll-like receptor (TLR) and nucleotide-binding-oligomerization domain (NOD) proteins, which are both involved in innate immune responses, in primary biliary epithelial cells isolated from the liver tissue of 10 patients with early-stage PSC, 12 patients with late-stage PSC, 10 patients with alcoholic liver disease (diseased controls) and 10 controls who had no liver disease.
Increased expression of TLR and NOD proteins was found in the primary biliary epithelial cells from patients with PSC or alcoholic liver disease compared with the healthy control individuals. The expression was stronger in patients in the late stages of PSC than in those in the early stages. Further analysis revealed that increased expression of TLR and NOD proteins could be attributable to the stimulatory effect of high levels of IFN-γ and tumor necrosis factor (TNF) in the livers of these patients. Increased expression of IFN-γ and TNF led to impaired inactivation of the TLR4 signalling cascade, which reduces endotoxin tolerance. When TNF was inhibited, the innate immune hyporesponsiveness was partially restored.
As the expression levels did not increase until the late stages of PSC, the authors believe these changes are not involved in the pathogenesis of chronic cholangitis, but could contribute to its progression.
ORIGINAL RESEARCH PAPER
Mueller, T. et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int. doi: 10.1111/j.1478-3231.2011.02635.x
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Greenhill, C. Inappropriate innate immune response to endotoxins contributes to chronic cholangitis. Nat Rev Gastroenterol Hepatol 8, 599 (2011). https://doi.org/10.1038/nrgastro.2011.185