Interleukin-4 deficiency promotes gallstone formation

Feeding interleukin-4 (IL-4) deficient C57BL/6 LDL receptor (LDLr)^-/- mice a modified diet to investigate the role of this cytokine in cholesterol metabolism led to an unexpected phenotype. IL-4^-/- → LDLr^-/- mice had enlarged gallbladders and an increased mortality that was preceded by acute body weight loss. To determine if IL-4 deficiency accounted for these findings, C57BL/6 IL-4^+/+ and IL-4^-/- mice were fed either a normal or modified diet. IL-4 deficiency did not alter bile composition or cause liver toxicity in mice fed a fat-enriched diet. Following 8 weeks of feeding a fat-enriched diet, no gallstones were detected in IL-4^+/+ mice, and only 20% had cholesterol crystals. In contrast, IL-4^-/- mice had a 100% incidence of gallstones and cholesterol crystals. IL-4^-/- deficiency also increased serum concentrations of bilirubin following feeding a fat-enriched diet. Therefore, these studies revealed an unexpected finding that IL-4 deficiency predisposes to gallstone formation.