Inflammatory cytokines alter human gallbladder epithelial cell absorption/secretion

Gallbladder inflammation is an early feature of gallstone formation in animal models. The inflammatory response is associated with increases in myeloperoxidase and interleukin (IL)-1 activities in the gallbladder wall. The present studies were designed to determine whether inflammatory cytokines directly affect gallbladder epithelial cell absorptive function. Studies were performed using cultured human gallbladder epithelial cells derived from a well-differentiated gallbladder carcinoma. Confluent monolayers were exposed to interleukin-1 (IL-1 alpha), IL-1 alpha plus its specific receptor inhibitor IL-1ra, tumor necrosis factor (TNF-alpha), lipopolysaccharide, or prostaglandin E-2. Unidirectional sodium and chloride fluxes were measured and used to calculate net ion fluxes. Compared to control monolayers, lipopolysaccharide, prostaglandin E-2, IL-1 alpha, and TNF-alpha decreased mucosal-to-serosal and net sodium and chloride fluxes and increased serosal-to-mucosal movement of sodium and unmeasured ions. The effects of IL-1 alpha were completely inhibited by its specific receptor antagonist IL-1ra. Similar to the proinflammatory agents lipopolysaccharide and prostaglandin E-2, the inflammatory cytokines IL-1 alpha and TNF-alpha directly affected gallbladder epithelial cell absorptive function. Because normal gallbladder absorptive function is protective against gallstone formation, alterations in absorptive function due to inflammation in the gallbladder wall may play a role in gallstone pathogenesis.