Background: The receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin super family of cell surface molecules. Except in lung, RAGE is expressed at low levels under normal physiological conditions in most tissues. RAGE has been implicated in the pathogenesis of inflammation and cancer.
Aims: i) To analyze the expression of RAGE in biliary and colonic mucosae obtained from cases of primary sclerosing cholangitis (PSC) with ulcerative colitis (UC). ii) To examine functional consequences of tissues exposed ex vivo to advanced glycation end products (AGE).
Methods: RAGE expression was determined by immunohistochemistry (IHC) on biliary tissues from cases of PSC (n=9) and compared with that of normal gallbladder mucosa (n=16). For colon, specimens from UC patients with PSC (n=8) was compared with normal colonic mucosa (n=8).
In separate experiments, functional responses of isolated tissues exposed to exogenous AGE (1μM) were examined with regard to ion transport, using electrophysiological techniques as well as cytokine elaboration using ELISA. Preparation of AGE was done by incubation of bovine serum albumin with glycoldehyde and confirmed by HPLC.
Results: IHC showed RAGE expression in epithelial cells of normal gallbladder. Epithelial RAGE expression was significantly down regulated in tissues obtained from patients with PSC.The above results were confirmed using Western blotting of snap frozen tissue samples. In contrast, colonic epithelial RAGE expression did not vary between the 2 groups (PSC/UC patients vs. control group).
In electrophysiological experiments using voltage clamped human colonic or gallbladder mucosa sheets, challenge with exogenous AGE (0.1–1.0 μM) did not influence short circuit current. AGE exposure had no effect upon ion transport responses to subsequent challenge with the cholinomimetic carbachol (0.01–10 μM) which was used to confirm tissue viability.
In separate experiments, exposure to AGE (1μM) stimulated IL 8 production from sheets of isolated gall bladder (261±45 ng/mg, treated tissues vs. 139±21 ng/mg, control; n=9, p=0.03) but not from colonic mucosa. Both the tissues released IL-8 in response to exogenous TNF.
Conclusions: RAGE is expressed in human gallbladder epithelium under normal physiological conditions & significantly down regulated in biliary epithelia of PSC. Patterns of RAGE in human colon are distinct, with no alteration in RAGE expression between normal and UC colon. In terms of function, AGE had no acute influence on electrogenic ion transport in either gallbladder or colonic epithelia. There are contrasting actions of AGE on chemokine release that may give insights into the disease.