The role of the IL6/gp130 system for liver disease progression

Streetz, Konrad L.; Wüestefeld, Torsten; Leifeld, Ludger; Tacke, Frank; Graw, A.; Kamino, K.; Schuetz, Gunnar; Mueller, W. H.; Manns, MP

doi:10.1016/s0168-8278(02)80184-2

Cited by 3 publications

(3 citation statements)

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“…After PH DNA synthesis was reduced in the surviving LPS-injected gp130-deleted animals, and the same phenotype was found when LPS was injected into IL6 Ϫ/Ϫ mice after PH. Consistent with this observation, hepatocyte-specific gp130 knockout animals are also hypersensitive to LPS indicating that gp130-dependent pathways in hepatocytes are essential for this observation (30).…”

Section: Discussionsupporting

confidence: 59%

Interleukin-6/Glycoprotein 130-dependent Pathways Are Protective during Liver Regeneration

Wüestefeld

Klein

Streetz

et al. 2003

Journal of Biological Chemistry

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After tissue loss the liver has the unique capacity to restore its mass by hepatocyte proliferation. Interleukin-6 (IL6)-deficient mice show a lack in DNA synthesis after partial hepatectomy (PH). To define better the role of IL6 and its family members for liver regeneration after PH, we used conditional knockout mice for glycoprotein 130 (gp130), the common signal transducer of all IL6 family members. We show that gp130-dependent pathways control Stat3 activation after PH. By using gene array analysis, we demonstrate that c-jun, NF-B, c-myc, and tumor necrosis factor receptor expression is gp130-dependent. However, in gp130-deleted mice only minor effects on cell cycle and on the maximum of DNA synthesis after PH were found compared with controls. As in conditional gp130 animals, the acute phase response was completely abolished, we considered that other means are essential to define the role of gp130-dependent pathways for liver regeneration. LPS stimulation in gp130-deleted and also IL6 ؊/؊ animals after PH leads to a significant reduction in survival and DNA synthesis, which was associated with decreased Bcl-xL expression and higher apoptosis in the liver. These results indicate that the phenotype concerning the reduction in DNA synthesis might be linked to the degree of infection after PH. Thus our results suggest that the role of gp130-dependent signaling is not a direct influence on cell cycle progression after partial hepatectomy but is to activate protective pathways important to enable hepatocyte proliferation.Interleukin 6 (IL6) 1 belongs to a family comprising of IL6, IL11, leukemia inhibitory factor, oncostatin M, ciliary neurotropic factor, and cardiotropin 1. They all need the gp130 molecule for signal transduction (1, 2). Knockout mice with deletion of individual cytokines of the IL6 family have a rather mild phenotype (3). Experiments elucidating the role of one specific cytokine of the IL6 family during different pathophysiological conditions are thus hampered by a potential redundancy in activity by another family member. Because all known IL6 family members use gp130 for signal transduction, mice lacking functional gp130 are an attractive model to study the role of IL6-related pathways in vivo.gp130 knockout mice die in uteri or directly after birth due to myocardial hypoplasia and reduced hemopoiesis in the fetal liver (4, 5). In order to circumvent this problem, conditional gp130 knockout mice using the Cre/loxP system were generated (6). In these mice exon 16 coding for the gp130 transmembrane domain can be deleted as two loxP sites flank it. In animals with the Cre recombinase under the control of the Mx promoter, expression is induced by interferon-␣ or agents triggering internal interferon-␣ expression, e.g. pIpC (6, 7).In the liver, IL6 is a major regulator of the acute phase response. It has also been shown that IL6 is essential for liver regeneration after partial hepatectomy (PH) (8, 9). First experiments indicated that there is an elevation of TNF␣ followed by IL6 in the serum of a...

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Section: Discussionsupporting

confidence: 59%

Interleukin-6/Glycoprotein 130-dependent Pathways Are Protective during Liver Regeneration

Wüestefeld

Klein

Streetz

et al. 2003

Journal of Biological Chemistry

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160

128

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“…In humans, IL-6 expression in the liver and in serum is significantly increased in patients with acute and chronic liver failure [31]. These observations in humans do not necessarily indicate that stimulation of IL-6-dependent pathways is also protective against human liver diseases.…”

Section: Discussionmentioning

confidence: 93%

ME3738 protects from concanavalin A‐induced liver failure via an IL‐6‐dependent mechanism

Klein¹,

Wüstefeld²,

Heinrich³

et al. 2003

Eur J Immunol

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ME3738 is a new compound that attenuates liver disease in several models of acute and chronic liver inflammation. We used the concanavalin A (Con A) model to elucidate the molecular mechanisms of ME3738 to block liver cell damage. Pretreatment of BALB/c mice with ME3738 prior to Con A injection resulted in a significant reduction in liver injury. The protective effect of ME3738 prior to Con A injection was associated with a reduction in IL-6 serum levels and NF-kappaB DNA binding in liver nuclear extracts. However, STAT3 DNA binding was induced via ME3738 prior to Con A injection. Further analysis showed that ME3738 induces IL-6 serum levels and activates STAT3 DNA binding and target gene transcription. The relevance of this finding was assessed in IL-6(-/-) mice. In these animals, ME3738 induced no increase in IL-6 serum expression, and activation of IL-6-dependent pathways was not found. In addition, ME3738 did not protect IL-6(-/-) animals from Con A-induced liver failure, while IL-6 injection was still effective. Therefore, we demonstrate that ME3738 triggers IL-6 expression, which activates pathways that are relevant to protect from Con A-induced liver failure.

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“…We and others could demonstrate a protective effect of gp130-dependent signaling, mainly mediated via STAT3 activation, in hepatocytes 17,18 but also in other cells, eg, immune cells. 19 At present, most studies have focused on mechanisms of acute liver injury, and only a few were designed to resolve the role of the IL-6/gp130 system during chronic liver injury.…”

Section: Discussionmentioning

confidence: 59%

Lack of Glycoprotein 130/Signal Transducer and Activator of Transcription 3-Mediated Signaling in Hepatocytes Enhances Chronic Liver Injury and Fibrosis Progression in a Model of Sclerosing Cholangitis

Plum

Tschaharganeh

Kroy

et al. 2010

The American Journal of Pathology

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The 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) model leads to chronic cholestatic liver injury and therefore resembles human diseases such as sclerosing cholangitis and forms of metabolic liver diseases. The role of the interleukin-6/glycoprotein 130 (gp130) system in this context is still undefined. Therefore, conditional gp130 knockout and knockin mice were used to achieve hepatocyte-specific deletions of gp130 (gp130 ⌬hepa ), gp130-dependent ras (gp130 ⌬hepaRas ), and signal transducer and activator of transcription (STAT) (gp130 ⌬hepaSTAT ) activation. These mice were treated with a DDC-containing diet and analyzed over time. Mice deficient in hepatic gp130 and STAT signaling showed increased and earlier mortality than wild-type and gp130⌬hepaRas animals. Over time, significantly more apoptosis and cholestasis became evident in gp130 ⌬hepa and gp130 ⌬hepaSTAT mice. These mice also displayed increased tumor necrosis factor-␣ expression, a diminished acute-phase response (lack of STAT3 and serum amyloid A activation), and enhanced immune cell infiltration in the liver. These were associated with stronger periportal oval cell activation. In addition, DDC treatment in gp130 ⌬hepa and gp130 Liver remodeling and fibrosis progression are often the result of an insufficient response of hepatocytes and biliary epithelial cells to different forms of chronic liver injury. A complex network of different liver and immune cells activates cytokines and growth factors, which trigger myofibroblasts to produce extracellular matrix proteins including collagen. Feeding mice 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) is a well established model to study such complex interactions in a highly relevant model of chronic cholestatic liver injury resembling certain metabolic, toxic, and cholestatic chronic liver diseases.1 Moreover, the model leads to a strong fibrotic response in the liver and can enhance the tumorigenic potential of proto-oncogenes.2 The model has also been used to study mechanisms of oval cell activation and proliferation. 3 The cholestatic phenotype of the model and its underlying pathobiology have only recently been elucidated in more detail.1 DDC feeding induces sclerosing cholangitisSupported by the Deutsche Forschungsgemeinschaft (grants 661/4-1 to K.L.S. and TRR57 to C.T.) and by the START program

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The role of the IL6/gp130 system for liver disease progression

Cited by 3 publications

References 0 publications

Interleukin-6/Glycoprotein 130-dependent Pathways Are Protective during Liver Regeneration

Interleukin-6/Glycoprotein 130-dependent Pathways Are Protective during Liver Regeneration

ME3738 protects from concanavalin A‐induced liver failure via an IL‐6‐dependent mechanism

Lack of Glycoprotein 130/Signal Transducer and Activator of Transcription 3-Mediated Signaling in Hepatocytes Enhances Chronic Liver Injury and Fibrosis Progression in a Model of Sclerosing Cholangitis

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