Interleukin-6 inhibits oxidative injury and necrosis after extreme liver resection

Jin, Xiaodong; Zhang, Zongxiu; Beer‐Stolz, Donna; Zimmers, Teresa A.; Koniaris, Leonidas G.

doi:10.1002/hep.21728

Cited by 76 publications

(65 citation statements)

References 40 publications

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“…In addition, mitochondrial abnormalities such as depletion of mitochondrial DNA, decreased activity of respiratory chain complexes, and impaired mitochondrial β-oxidation and mitochondrial DNA complexes have been observed in patients with non-alcoholic fatty liver disease [48,49]. IL-6 treatment has previously been shown to decrease oxidative injury after 87% hepatectomy in mice [50]. Using GSEA, we demonstrated here that global deletion of IL-6 in mice resulted in a co-ordinate downregulation of genes associated with the tricarboxylic acid cycle, the electron transport chain and oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

et al. 2010

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Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 −/− ) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 −/− and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 −/− mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 −/− and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 −/− mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 −/− relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

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Section: Discussionmentioning

confidence: 99%

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

et al. 2010

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“…[9][10][11] Mice that are deficient in IL-6 have an impaired ability to regenerate their livers after partial hepatectomy and also show reduced hepatic expression of the antiapoptotic mediators Bcl-2, Bcl-xL and Ref-1 (see ref. 5,[10][11][12].…”

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confidence: 99%

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Yamaguchi

Itoh

Yokomizo

et al. 2011

Laboratory Investigation

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Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3 À/À or GP130 À/À mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD dietfed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.

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“…The survival study was performed on 10 rats in each group. Cell signaling involved in proliferation, differentiation and apoptosis was confirmed at the early postoperative period after liver surgery and subsequently progressive necrosis was observed, as described previously [3,12,13,18,[29][30][31] . Serum and plasma were collected at 6 h after surgery (n = 5, in each group).…”

Section: Methodsmentioning

confidence: 65%

“…In particular, many researchers have focused on TIMP-1 and TIMP-2 during liver regeneration [25][26][27][28] . Although shear stress with portal hypertension and CIWR injury trigger the liver regeneration cascade after liver surgery, these injuries also cause fatal liver damage [29][30][31] . Initial damage is confirmed at the early postoperative period after liver surgery [3,12,13,18,[29][30][31] .…”

Section: Introductionmentioning

confidence: 99%

“…Although shear stress with portal hypertension and CIWR injury trigger the liver regeneration cascade after liver surgery, these injuries also cause fatal liver damage [29][30][31] . Initial damage is confirmed at the early postoperative period after liver surgery [3,12,13,18,[29][30][31] . Therapeutic strategies to reduce this damage have the advantage of improving clinical results after liver surgery and overcoming the current issue of insufficient liver volume in the field of liver surgery.…”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

Hori¹,

Üemoto²,

Chen³

et al. 2014

WJH

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AIM:To investigate oxidative stress (OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage. METHODS:Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant (60% hepatectomy); orthotopic liver transplantation (OLT) with whole liver graft (100% OLT); and split OLT (SOLT) with 40% graft (40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OSinduced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase (PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography. RESULTS:Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT. CONCLUSION: Under conditions with an insufficient liver remnant, prevention of OS-induced damage viathe Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery. Hori T et al . Hepatic damage after liver surgeryCore tip: Although shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery, these injuries also cause fatal liver damage. Postoperative liver damage is still a critical matter in the field of liver surgery. Oxidative stress and extracellular matrices are important for liver regeneration after surgery and these may be important keys to overcome current problems in the field of liver surgery. Here, we investigated oxidative stress-mediated damage and the behavior of extracellular matrices in various rat models with liver surgery.Hori T, Uemoto S, Chen F, Gardner LB, Baine AMT, Hata T, Kogure T, Nguyen JH. ��idative stress and e�tracellular ma��idative stress and e�tracellular matrices after hepatectomy and liver transplantation in rats. World

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Interleukin-6 inhibits oxidative injury and necrosis after extreme liver resection

Cited by 76 publications

References 40 publications

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Oxidative stress and extracellular matrices after hepatectomy and liver transplantation in rats

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