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

Liu, Zejin; Sakamoto, Takaaki; Yokomuro, Shigeki; Ezure, Tsukasa; Субботин, Владимир; Murase, Noriko; Contrucci, Sarah; Demetris, Anthony J.

doi:10.1034/j.1600-0676.2000.020002114.x

Cited by 40 publications

(42 citation statements)

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“…25 However, an absolute decrease in hepatocytes does not occur 39 or is less than anticipated, because chronic compensatory mechanisms ensure that hepatocytes continue to proliferate, 40,41 and there is an overall increase in liver size. 25,42 Results from this study are consistent with previous studies from our laboratory 21 showing that despite brisk upregulation of IL-6 within hours after BDL, the initial increase in liver mass during the first week is not IL-6-dependent. An increase in liver mass from the normal 4.5-5.0% to a maximum of 7.5-8.0% of total body weight occurred in both the IL-6 ϩ/ϩ and IL-6 Ϫ/Ϫ mice.…”

Section: Discussionsupporting

confidence: 82%

“…During the first week, an equivalent and sharp increase in serum ALT levels, indicative of liver cell injury, was already evident in both groups when first measured at 16 hours and peaked at 48 hours, 21 a finding similar to that of our previous study in C57BL/6 mice. 20 At 3 weeks, serum ALT levels had decreased considerably in both groups but was higher in the IL-6 Ϫ/Ϫ mice than in the IL-6 ϩ/ϩ mice ( Figure 1b).…”

Section: Morbidity Liver Injury Tests Mortality and Bile Colorsupporting

confidence: 80%

“…[45][46][47][48] The IL-6 Ϫ/Ϫ mice attempt to compensate for the lack of IL-6 after BDL with up-regulation of LIF, which is also a BEC mitogen, in vitro. 21 As expected, preliminary data on the quantitative level of LIF mRNA production from a ribonuclease protection assay showed higher levels in the IL-6 Ϫ/Ϫ mice at 12 weeks after BDL (data not shown). Despite the increase in LIF and possibly other gp130 ligands in the IL-6 Ϫ/Ϫ mice after BDL, whole-liver gp130 protein expression, gp130 phosphorylation, and downstream signaling through nuclear phospho-STAT3 are lower than in the IL-6 ϩ/ϩ mice.…”

Section: Discussionmentioning

confidence: 54%

“…19 Obstructive cholangiopathy is associated with biomechanical stress of the biliary tree and an increased expression of the IL-6/gp80/gp130 receptor-ligand signaling system. 20,21 We therefore tested the hypothesis that the absence of IL-6 would lead to phenotypic alterations in the response to long-term bile duct ligation (BDL). This was accomplished by subjecting homozygous IL-6 Ϫ/Ϫ mice and wild-type IL-6 ϩ/ϩ (littermate) controls to longterm BDL for 12 weeks.…”

mentioning

confidence: 99%

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

Ezure

Sakamoto

Tsuji

et al. 2000

The American Journal of Pathology

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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. Interleukin-6 (IL-6)/gp-130 signaling is involved acutely in hepatocyte 1,2 and biliary epithelial cell (BEC) growth control and pathobiology. For example, liver regeneration after partial hepatectomy (PH) is delayed in IL-6 Ϫ/Ϫ mice, 1,2 whereas IL-6/sIL-6R double transgenic mice develop hepatocellular hyperplasia and adenomas. 3 Although data on the in vitro effects of IL-6 on hepatocyte proliferation are conflicting, 4,5 there are at least two mechanisms by which IL-6/gp-130 promotes BEC growth in vitro. IL-6 is able to directly stimulate BEC DNA synthesis 6 and inhibit apoptosis, via an increase of the bcl-2/ bax ratio. 7 When stimulated by other proinflammatory cytokines or phorbol esters, nonneoplastic BEC can also produce and secrete IL-6, which can then act as an autocrine growth factor under conditions of BEC stress. 6,8,9 Serum and liver IL-6 levels are also elevated in patients with chronic inflammatory liver diseases. 10 -13 In this setting, IL-6 has traditionally been considered to exert a profibrogenic and mitoinhibitory influence on the development of cirrhosis. 10,14 -17 However, in other "chronic inflammatory proliferative disorders," such as psoriasis and rheumatoid arthritis, IL-6 has been linked with keratinocyte and synovial cell proliferation, respectively. 18 In addition, recent studies have shown that gp130 sign...

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Section: Discussionsupporting

confidence: 82%

Section: Morbidity Liver Injury Tests Mortality and Bile Colorsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

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

Ezure

Sakamoto

Tsuji

et al. 2000

The American Journal of Pathology

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“…Whole liver, including equal amounts of perihilar tissue, was used for RNA and protein isolation. Some of the analyses on whole mouse liver after BDL were conducted on tissues saved from previous experiments, 7,14 but none of the results have been previously reported.…”

Section: Operative Procedures and Isolation Of The Biliary Treementioning

confidence: 99%

Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Nozaki

Lunz

Specht

et al. 2004

The American Journal of Pathology

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Microarray analysis identified trefoil factor family 3 (TFF3) as a gene expressed in biliary epithelial cells (BECs), regulated by interleukin (IL)-6, and potentially involved in biliary pathophysiology. We therefore studied the regulation and function of BEC TFF3, in vitro and in vivo in IL-6 ؉/؉ and IL-6 ؊/؊ mice subjected to chronic bile duct ligation for 12 weeks. In vitro studies showed that IL-6 wild-type (IL-6 ؉/؉ ) BECs expressed higher TFF3 mRNA and protein levels than IL-6-deficient (IL-6 ؊/؊ ) BECs. BEC TFF3 expression is dependent primarily on signal transducer and activator of transcription (STAT3) signaling, but the reciprocal negative regulation known to exist between the intracellular IL-6/gp130 signaling pathways, STAT3 and mitogen-activated protein kinase (MAPK), importantly contributes to BEC TFF3 expression. Specifically blocking STAT3 activity with a dominant-negative molecule or treatment with a growth factor such as hepatocyte growth factor, which increases MAPK signaling, decreases BEC TFF3 expression. In contrast, specifically blocking MAPK activity with PD98059 significantly increased BEC TFF3 expression. Higher BEC TFF3 levels in IL-6 ؉/؉ BECs were associated with significantly better migration than IL-6 ؊/؊ BECs in a wound-healing assay and defective IL-6 ؊/؊ BEC migration was reversed with exogenous TFF3. In vivo, hepatic TFF3 mRNA and protein expression was limited to BECs and dependent significantly on STAT3 signaling, but was influenced by other factors present after bile duct ligation. Com-

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Characterization of time-related changes after experimental bile duct ligation

Georgiev

Jochum

Heinrich

et al. 2008

British Journal of Surgery

207

184

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

Cited by 40 publications

References 0 publications

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

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

Regulation and Function of Trefoil Factor Family 3 Expression in the Biliary Tree

Characterization of time-related changes after experimental bile duct ligation

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