Interleukin‐6 inhibits cell proliferation in a rat model of hepatocellular carcinoma

Moran, Diarmuid M.; Mayes, Nicholas; Koniaris, Leonidas G.; Cahill, Paul A.; McKillop, Iain H.

doi:10.1111/j.1478-3231.2005.01083.x

Cited by 25 publications

(30 citation statements)

References 52 publications

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“…Densitometeric analysis of signal intensity was analyzed using the EDAS-290 system (Kodak, Rochester, NY) as previously (13). In the instance of antibodies against phosphorylated proteins (pERK1/2, pSTAT 3) signal intensity was corrected to total protein detection (ERK1/2, STAT 3).…”

Section: Data Analysis and Statisticsmentioning

confidence: 99%

“…Protein concentrations were equalized and samples boiled with Laemmli buffer. Samples were then analyzed by Western blot as previously (13). Primary antibodies were used at a dilution of 1:1000 with the exception of anti-pSTAT 3 (1:2000).…”

Section: Preparation Of Cell Lysates and Immunoblottingmentioning

confidence: 99%

“…Secondary antibodies were used at a dilution of 1:5000. Detection was performed using ECL and X-ray film as previously (13).…”

Section: Preparation Of Cell Lysates and Immunoblottingmentioning

confidence: 99%

“…Previous studies by our group have identified altered expression of IL-6 signaling components in a rat model of HCC in vitro and in vivo. Furthermore, treatment of these HCC cells with IL-6 inhibits cellular proliferation (13). The aim of the current study is to determine the cell cycle regulatory effects of IL-6 in mediating inhibition of proliferation in this rat model of HCC.…”

Section: Introductionmentioning

confidence: 99%

“…In this instance Src homology protein 2 tyrosine phosphatase-2 (SHP-2) binds to activated gp130 and stimulates the small G-protein signaling molecule p 21 ras. Following p 21 ras activation, via GTP displacement of GDP activation of intracellular MAPKs (MAPK) signaling cascades, including p42/p44 extracellular signal regulated kinase (p42/44 ERK) (10)(11)(12)(13). Active STAT 3, in collaboration with other transcription factors, enhances the expression of nuclear factors enabling resting hepatocytes to respond to other growth factors and proliferate (10,11).…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-6 Mediates G0/G1 Growth Arrest in Hepatocellular Carcinoma Through a STAT 3-Dependent Pathway

Moran

Mattocks

Cahill

et al. 2008

Journal of Surgical Research

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Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates diverse cell functions including proliferation and differentiation. Within the liver IL-6 signaling plays a central role during normal hepatic growth and regeneration yet can inhibit the proliferation of hepatocellular carcinoma (HCC) cells. The aim of the current study was to identify underlying mechanisms whereby IL-6 induces cell cycle arrest in HCC cells. These studies demonstrate that IL-6 inhibits cell cycle progression at the G0/G1 interface through inhibition of cyclin dependent kinase (cdk) 2 and cdk4 activity in the absence of changes in total cyclin (A, D1, D3 and E) or cdk (cdk2, 4 and cdc2 p34) expression. Inhibition of signal transduction pathways associated with IL-6 receptor activation demonstrate that IL-6-dependent inhibition of G0-G1 progression occurs via Janus tyrosine kinase-signal transducers and activators of transcription-3 (Jak-STAT3)-dependent induction of p21 waf1/cip1 and is independent of ERK-MAPK signaling. These data demonstrate that, while IL-6 plays a central role in hepatocyte priming and proliferation in vivo, the pronounced inhibition of proliferation observed in HCC cells occurs due to IL-6-STAT3-dependent regulation of cdk2/cdk4 activity and p21 waf1/cip1 expression.

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Section: Data Analysis and Statisticsmentioning

confidence: 99%

Section: Preparation Of Cell Lysates and Immunoblottingmentioning

confidence: 99%

“…Secondary antibodies were used at a dilution of 1:5000. Detection was performed using ECL and X-ray film as previously (13).…”

Section: Preparation Of Cell Lysates and Immunoblottingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Interleukin-6 Mediates G0/G1 Growth Arrest in Hepatocellular Carcinoma Through a STAT 3-Dependent Pathway

Moran

Mattocks

Cahill

et al. 2008

Journal of Surgical Research

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IL‐6(−572/−597) polymorphism and expression in HBV disease chronicity in an Indian population

Saxena

Chawla

Verma

et al. 2014

American J Hum Biol

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Deletion of Interleukin-6 in Mice With the Dominant Negative Form of Transforming Growth Factor β Receptor II Improves Colitis but Exacerbates Autoimmune Cholangitis

et al. 2010

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The role of interleukin-6 (IL-6) in autoimmunity attracts attention because of the clinical usage of monoclonal antibodies to IL-6 receptor (IL-6R), designed to block IL-6 pathways. In autoimmune liver disease, activation of the hepatocyte IL-6/STAT3 (signal transducer and activator of transcription 3) pathway is associated with modulating pathology in acute liver failure, in liver regeneration, and in the murine model of concanavalin A–induced liver inflammation. We have reported that mice expressing a dominant negative form of transforming growth factor β receptor II (dnTGFβRII) under control of the CD4 promoter develop both colitis and autoimmune cholangitis with elevated serum levels of IL-6. Based on this observation, we generated IL-6–deficient mice on a dnTGF-βRII background (dnTGFβRII IL-6−/−) and examined for the presence of antimitochondrial antibodies, levels of cytokines, histopathology, and immunohistochemistry of liver and colon tissues. As expected, based on reports of the use of anti–IL-6R in inflammatory bowel disease, dnTGFβRII IL-6−/− mice manifest a dramatic improvement in their inflammatory bowel disease, including reduced diarrhea and significant reduction in intestinal lymphocytic infiltrates. Importantly, however, autoimmune cholangitis in dnTGFβRII IL-6−/− mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology. Conclusion: The data from these observations emphasize that there are distinct mechanisms involved in inducing pathology in inflammatory bowel disease compared to autoimmune cholangitis. These data also suggest that patients with inflammatory bowel disease may not be the best candidates for treatment with anti–IL-6R if they have accompanying autoimmune liver disease and emphasize caution for therapeutic use of anti–IL-6R antibody. Hepatology 2010

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Interleukin‐6 inhibits cell proliferation in a rat model of hepatocellular carcinoma

Cited by 25 publications

References 52 publications

Interleukin-6 Mediates G0/G1 Growth Arrest in Hepatocellular Carcinoma Through a STAT 3-Dependent Pathway

Interleukin-6 Mediates G0/G1 Growth Arrest in Hepatocellular Carcinoma Through a STAT 3-Dependent Pathway

IL‐6(−572/−597) polymorphism and expression in HBV disease chronicity in an Indian population

Deletion of Interleukin-6 in Mice With the Dominant Negative Form of Transforming Growth Factor β Receptor II Improves Colitis but Exacerbates Autoimmune Cholangitis

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