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

Aim: The hypothesis that interleukin-6-IL-6/gp130 signaling is involved in liver and biliary epithelial cell (BEC) biology and growth control was test ed by subjecting homozygous IL-6 deficient mice (IL-6(-/) (-)) and wild typ e (IL-6(+/+)) littermate controls to bile duct ligation (BDL). Materials an d methods: During the first week after BDL, the two groups were compared wi th respect to routine liver injury tests, liver histology, BEC and hepatocy te DNA synthesis, together with the expression of mRNA and protein of IL-6 as well as related growth factors, and their receptors. Results. During the first week after BDL, there was marked upregulation of IL-6 mRNA and prote in 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 ce lls 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 BEG. 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(-/-) mic e 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 slightl y less HGF mRNA and protein expression in the IL-6-/- mice, but the differe nces were not significant. Leukemia inhibitory factor (LIF), another gp-130 ligand, also showed marked peri-biliary upregulation after BDL in both gro ups, and also induced BEC DNA synthesis, in vitro. Conclusions: The mild ph enotypical differences between IL-6(+/+) and IL-6(-/-) mice in the acute re sponse to BDL is most likely attributable to the redundancy of the gp-130 s ignaling system. However, the long-term response to BDL results in a distin ct phenotype in the IL-6(-/-) mice, marked by a relentless rise in serum to tal bilirubin and an inability to maintain compensatory increase in liver m ass.