Acute obstructive cholangiopathy in interleukin‐6 deficient mice: compensation by leukemia inhibitory factor (LIF) suggests importance of gp‐130 signaling in the ductular reaction

Abstract

The hypothesis that interleukin-6-IL-6/gp130 signaling is involved in liver and biliary epithelial cell (BEC) biology and growth control was tested by subjecting homozygous IL-6 deficient mice (IL-6-/-) and wild type (IL-6+/+) littermate controls to bile duct ligation (BDL). During the first week after BDL, the two groups were compared with respect to routine liver injury tests, liver histology, BEC and hepatocyte DNA synthesis, together with the expression of mRNA and protein of IL-6 as well as related growth factors, and their receptors. During the first week after BDL, there was marked upregulation of IL-6 mRNA and protein in the IL-6+/+ mice only in the vicinity of the biliary tree; whereas, biliary/peri-biliary IL-6R, HGF and met mRNA and protein increased in both groups. IL-6, HGF mRNA and protein localized to periductal inflammatory cells and stellate cells, while met and IL-6R protein were upregulated in the BEC and, to a lesser extent, in hepatocytes. This occurred during maximal proliferation of the BEC. Despite the absence of IL-6 in the IL-6-/- mice, there were only mildly phenotypic differences between the two groups, and no differences in mortality. Compared to IL-6+/+ controls, IL-6-/- mice showed slightly less BEC proliferation, a trend toward more liver injury, and significantly higher total serum bilirubin (TB) levels, suggestive of impaired biliary tree integrity. These changes were associated with slightly less HGF mRNA and protein expression in the IL-6-/- mice, but the differences were not significant. Leukemia inhibitory factor (LIF), another gp-130 ligand, also showed marked peri-biliary upregulation after BDL in both groups, and also induced BEC DNA synthesis, in vitro. The mild phenotypical differences between IL-6+/+ and IL-6-/- mice in the acute response to BDL is most likely attributable to the redundancy of the gp-130 signaling system. However, the long-term response to BDL results in a distinct phenotype in the IL-6-/- mice, marked by a relentless rise in serum total bilirubin and an inability to maintain compensatory increase in liver mass.