The Development and Compensation of Biliary Cirrhosis in Interleukin-6-deficient Mice

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2000 May 4

PMID 10793074

Citations 41

Authors

T Ezure

T Sakamoto

H Tsuji

J G Lunz 3rd

N Murase

J J Fung

A J Demetris

Affiliations

Soon will be listed here.

Abstract

In an effort to understand the role of IL-6/gp130 signaling in chronic liver injury, IL-6 deficient (IL-6(-/-)) and wild-type control (IL-6(+/+)) mice were subjected to bile duct ligation (BDL) for 12 weeks. This maneuver causes chronic biomechanical stress and liver injury, fueling sustained biliary epithelial and hepatocyte proliferation. By 12 weeks after BDL, IL-6(-/-) mice develop significantly higher total serum bilirubin levels (23.2 +/- 2.3 versus 14.9 +/- 2.1 mg/dl, P < 0.0001; delta bilirubin subfraction 16.7 +/- 4.0% versus 9.2 +/- 1.8%; P < 0.002), and the majority (15/18) show "black" gallbladder bile, compared to IL-6(+/+) mice (5/16; P < 0.003). The IL-6(-/-) mice also cannot sustain the compensatory liver mass increase commonly seen with chronic obstructive cholangiopathy, because of less hepatocyte proliferation, despite a rate of hepatocyte apoptosis similar to that of IL-6(+/+) mice. Moreover, IL-6(-/-) mice show a more advanced stage of biliary fibrosis and a higher mortality rate than the IL-6(+/+) controls (51% versus 23%; P < 0.02). These phenotypic changes in the IL-6(-/-) mice are associated with decreased expression and phosphorylation of gp130 and the transcription factor STAT3, compared to IL-6(+/+) mice. Daily treatment with exogenous recombinant IL-6 for 3-6 weeks starting at 6 weeks after BDL significantly lowers the serum total bilirubin in both groups. In the IL-6(-/-) mice, exogenous IL-6 treatment also increases the level of gp130 protein expression and completely reverses the loss of liver mass by increasing the hepatocyte proliferation. In conclusion, IL-6 appears to contribute to biliary tree integrity and maintenance of hepatocyte mass during chronic injury.

Citing Articles

Establishment of a mouse model for bile duct repair and tissue engineering.

Ge X, Xu D, Pan K, Mao G, Lu S, Li C Exp Ther Med. 2022; 24(6):739.

PMID: 36478886 PMC: 9716339. DOI: 10.3892/etm.2022.11675.

Fibrotic Events in the Progression of Cholestatic Liver Disease.

Wu H, Chen C, Ziani S, Nelson L, Avila M, Nevzorova Y Cells. 2021; 10(5).

PMID: 34062960 PMC: 8147992. DOI: 10.3390/cells10051107.

The two facets of gp130 signalling in liver tumorigenesis.

Schmidt-Arras D, Galun E, Rose-John S Semin Immunopathol. 2021; 43(4):609-624.

PMID: 34047814 PMC: 8443519. DOI: 10.1007/s00281-021-00861-0.

Network Pharmacology-Based Investigation of the Therapeutic Mechanisms of Action of Danning Tablets in Nonalcoholic Fatty Liver Disease.

Lin T, Li L, Liang C, Peng L Evid Based Complement Alternat Med. 2021; 2021:3495360.

PMID: 33995543 PMC: 8096548. DOI: 10.1155/2021/3495360.

Comparing distress of mouse models for liver damage.

Tang G, Seume N, Hager C, Kumstel S, Abshagen K, Bleich A Sci Rep. 2020; 10(1):19814.

PMID: 33188220 PMC: 7666197. DOI: 10.1038/s41598-020-76391-w.

References

Hirota H, Chen J, Betz U, Rajewsky K, Gu Y, ROSS Jr J . Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell. 1999; 97(2):189-98. DOI: 10.1016/s0092-8674(00)80729-1. View

Peters M, Jacobs S, Ehlers M, Vollmer P, Mullberg J, Wolf E . The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J Exp Med. 1996; 183(4):1399-406. PMC: 2192475. DOI: 10.1084/jem.183.4.1399. View

Huggett A, Ford C, Thorgeirsson S . Effects of interleukin-6 on the growth of normal and transformed rat liver cells in culture. Growth Factors. 1989; 2(1):83-9. DOI: 10.3109/08977198909069084. View

Murray R, McGuigan F, Grant S, Reid D, Ralston S . Polymorphisms of the interleukin-6 gene are associated with bone mineral density. Bone. 1997; 21(1):89-92. DOI: 10.1016/s8756-3282(97)00081-1. View

Shibata M, Watanabe M, Ueno Y, Sadamoto T, Sato G, Yasushi T . Clinicopathological study of proliferating cell nuclear antigen (PCNA) of hepatocytes in primary biliary cirrhosis. J Gastroenterol. 1994; 29(1):56-60. DOI: 10.1007/BF01229074. View

Tuchweber B, Desmouliere A, Bochaton-Piallat M, Rubbia-Brandt L, Gabbiani G . Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat. Lab Invest. 1996; 74(1):265-78. View

Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin J, Humphries S . The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998; 102(7):1369-76. PMC: 508984. DOI: 10.1172/JCI2629. View

Gall J, Bhathal P . A quantitative analysis of the liver following ligation of the common bile duct. Liver. 1990; 10(2):116-25. DOI: 10.1111/j.1600-0676.1990.tb00444.x. View

Napoli J, Bishop G, McCaughan G . Increased intrahepatic messenger RNA expression of interleukins 2, 6, and 8 in human cirrhosis. Gastroenterology. 1994; 107(3):789-98. DOI: 10.1016/0016-5085(94)90128-7. View

10.

Saito M, Yoshida K, Hibi M, Taga T, Kishimoto T . Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992; 148(12):4066-71. View

11.

Liu Y, Beedle A, Lin L, Bell A, Zarnegar R . Identification of a cell-type-specific transcriptional repressor in the promoter region of the mouse hepatocyte growth factor gene. Mol Cell Biol. 1994; 14(11):7046-58. PMC: 359238. DOI: 10.1128/mcb.14.11.7046-7058.1994. View

12.

Kountouras J, Billing B, Scheuer P . Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat. Br J Exp Pathol. 1984; 65(3):305-11. PMC: 2040968. View

13.

Kuma S, Inaba M, Ogata H, Inaba K, Okumura T, Saito K . Effect of human recombinant interleukin-6 on the proliferation of mouse hepatocytes in the primary culture. Immunobiology. 1990; 180(2-3):235-42. DOI: 10.1016/s0171-2985(11)80331-1. View

14.

Skelly S, Tackney C, Hicklin D, Tamkins T, Goldstein N, Waksal H . High-level expression of a biologically active human interleukin-6 mutein. J Biotechnol. 1994; 34(1):79-86. DOI: 10.1016/0168-1656(94)90168-6. View

15.

Tiggelman A, Boers W, Linthorst C, Brand H, Sala M, Chamuleau R . Interleukin-6 production by human liver (myo)fibroblasts in culture. Evidence for a regulatory role of LPS, IL-1 beta and TNF alpha. J Hepatol. 1995; 23(3):295-306. View

16.

Omori N, Evarts R, Omori M, Hu Z, Marsden E, Thorgeirsson S . Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. Lab Invest. 1996; 75(1):15-24. View

17.

Polimeno L, Azzarone A, Zeng Q, Panella C, Subbotin V, Carr B . Cell proliferation and oncogene expression after bile duct ligation in the rat: evidence of a specific growth effect on bile duct cells. Hepatology. 1995; 21(4):1070-8. PMC: 2963564. View

18.

Hashmonai M, Kam I, SCHRAMEK A . The etiology of "white bile" in the biliary tree. J Surg Res. 1984; 37(6):479-86. DOI: 10.1016/0022-4804(84)90217-8. View

19.

Belle S, Beringer K, Detre K . Recent findings concerning liver transplantation in the United States. Clin Transpl. 1996; :15-29. View

20.

Yasoshima M, Kono N, Sugawara H, Katayanagi K, Harada K, Nakanuma Y . Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells: in situ and culture study. Lab Invest. 1998; 78(1):89-100. View