Role of IL-6 trans-signaling in CCl4 induced liver damage

Gewiese-Rabsch, Jessica; Drucker, Claudia; Malchow, Sven; Scheller, Jürgen; Rose-John, Stefan

doi:10.1016/j.bbadis.2010.07.023

Cited by 38 publications

(29 citation statements)

References 31 publications

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“…IL-6 also binds to both membrane-bound IL-6 receptor and soluble IL-6 receptor to trigger NF-κB- and STAT3-dependent hepatic regeneration [36, 37]. TGF-β 1 is mainly a pro-fibrotic factor in chronic liver disease, e.g., fatty liver disease.…”

Section: Discussionmentioning

confidence: 99%

S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice

et al. 2011

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PurposeTo study the protective effects and underlying molecular mechanisms of SAMC on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in the mouse model.MethodsMice were intraperitoneally injected with CCl4 (50 μl/kg; single dose) to induce acute hepatotoxicity with or without a 2-h pre-treatment of SAMC intraperitoneal injection (200 mg/kg; single dose). After 8 h, the blood serum and liver samples of mice were collected and subjected to measurements of histological and molecular parameters of hepatotoxicity.ResultsSAMC reduced CCl4-triggered cellular necrosis and inflammation in the liver under histological analysis. Since co-treatment of SAMC and CCl4 enhanced the expressions of antioxidant enzymes, reduced the nitric oxide (NO)-dependent oxidative stress, and inhibited lipid peroxidation induced by CCl4. SAMC played an essential antioxidative role during CCl4-induced hepatotoxicity. Administration of SAMC also ameliorated hepatic inflammation induced by CCl4 via inhibiting the activity of NF-κB subunits p50 and p65, thus reducing the expressions of pro-inflammatory cytokines, mediators, and chemokines, as well as promoting pro-regenerative factors at both transcriptional and translational levels.ConclusionsOur results indicate that SAMC mitigates cellular damage, oxidative stress, and inflammation in CCl4-induced acute hepatotoxicity mouse model through regulation of NF-κB. Garlic or garlic derivatives may therefore be a potential food supplement in the prevention of liver damage.

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Section: Discussionmentioning

confidence: 99%

S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice

et al. 2011

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“…Aldeguer et al characterized a paracrine mechanism by which cells of bone marrow origin, most likely Kupffer cells, regulated the regenerative capacity of hepatocytes through IL-6 expression [29]. Gewiese-Rabsch et al demonstrated that IL-6 trans-signaling via soluble IL-6R was important for the physiological response of the liver to CCl4-induced chemical damage [26]. Kawasaki et al reported that platelets promoted liver-specific endothelium cell proliferation and induced IL-6 and vascular endothelial growth factor production.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 Mediates Angiotensinogen Gene Expression during Liver Regeneration

et al. 2013

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BackgroundAngiotensinogen is the precursor of angiotensin II, which is associated with ischemia-reperfusion injury. Angiotensin II reduces liver regeneration after hepatectomy and causes dysfunction and failure of reduced-size liver transplants. However, the regulation of angiotensinogen during liver regeneration is still unclear.AimsTo investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.MethodsA mouse in vitro partial hepatectomy animal model was used to evaluate the expression of interleukin-6 (IL-6) and angiotensinogen during liver regeneration. Serum IL-6 and angiotensinogen were detected by enzyme immunoassay (EIA). Angiotensinogen mRNA was detected by RT-PCR. Tissue levels of angiotensinogen protein were detected by Western blot analysis. Primary cultures of mouse hepatocytes were used to investigate IL-6-induced angiotensinogen. Chemical inhibitors were used to perturb signal transduction pathways. Synthetic double-stranded oligodeoxynucleotides (ODNs) were used as ‘decoy’ cis-elements to investigate transcription. Ki 67 staining and quantification were used to verify liver regeneration.ResultsIn the in vivo model, the levels of serum IL-6 and angiotensinogen correlated. In the in vitro model, IL-6 transcriptionally regulated angiotensinogen expression. Additionally, IL-6 mediated angiotensinogen expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and JAK/p38 signaling. Decoy ODN analyses revealed that STAT3 and nuclear factor-kB (NF-kB) also played critical roles in the transcriptional regulation of angiotensinogen by IL-6. IL-6-mediated signaling, JAK2, STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice.ConclusionDuring liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the JAK/STAT3 and JAK/p38/NF-kB signaling pathways. Interruption of the molecular mechanisms of angiotensinogen regulation may be applied as the basis of therapeutic strategies for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.

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“…Thus, the findings of focal hepatocyte necrosis surrounded by either hemorrhages or inflammatory infiltrates in the patients were considered as direct histological evidence of drug toxicity related to the tocilizumab and anakinra. It has been suggested that the hepatic necrosis due to anakinra is a T-cell-dependent apoptotic immune-mediated response 9,10…”

Section: Discussionmentioning

confidence: 99%

Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions

Mahmud¹,

Mader²,

Safadi³

2011

CPAA

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BackgroundElevation of liver enzymes in rheumatoid arthritis patients treated with tocilizumab (Actemra®) or anakinra (Kineret®) is a well-documented phenomenon. However, characterization of liver histology has not been defined in most cases. Similarly, the factors involved in decisions regarding discontinuation of treatment and outcome have not been discussed in the literature to any significant extent.CasesTwo women with rheumatoid arthritis refractory to standard therapies are reported here. One was treated with tocilizumab and the other with anakinra, and both developed toxic liver effects. Liver biopsy in both cases showed focal necrosis of hepatocytes – a hallmark of drug toxicity – with steatosis and early fibrosis. Inflammatory infiltrates were prominent in the patient treated with anakinra but not in the tocilizumab-treated patient. However, FibroTest (Assistance publique – Hôpitaux de Paris, Paris, France) in the latter patient showed an inflammatory activity of A2 and was staged as F2, and the histology also showed hemorrhagic areas. Although both patients were overweight and both had been exposed to steroids, the steatosis and steatohepatitis were considered to be related to drug hepatotoxicity. Other possible etiologies for liver injury were excluded. Discontinuation of anakinra led to rapid normalization of liver enzymes. The patient receiving tocilizumab developed hepatosplenomegaly but had normal liver enzymes. In spite of the hepatosplenomegaly, the tocilizumab treatment was continued since the patient had not responded to other drugs. There was a good response to the tocilizumab treatment and the liver biopsy showed only insignificant, reversible liver injury. At follow-up at 6-months the patient remains stable.ConclusionAs cases showing tocilizumab or anakinra liver toxicity are appearing more frequently to the authors, a full assessment for liver injury is recommended in patients given those drugs, with careful consideration of the decision to continue or discontinue treatment. Further studies with long-term follow-up analysis are mandatory to guide appropriate management strategies.

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Role of IL-6 trans-signaling in CCl4 induced liver damage

Cited by 38 publications

References 31 publications

S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice

S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice

Interleukin-6 Mediates Angiotensinogen Gene Expression during Liver Regeneration

Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions

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