Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration

Peters, Malte; Blinn, Guido; Jostock, Thomas; Schirmacher, Peter; Büschenfelde, Karl‐Hermann Meyer zum; Galle, Peter R.; Rose–John, Stefan

doi:10.1053/gast.2000.20236

Cited by 114 publications

(84 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[4][5][6][7] More recently, investigators have also examined the potential therapeutic application of IL-6 and a linked IL-6 co-receptor complex (termed "super-IL-6") in liver disease. 16 As demonstrated herein, exogenous IL-6 may accelerate recovery of liver mass in vivo, consistent with findings that IL-6 may have therapeutic application in the prevention of ischemic injury during organ preservation before transplantation and in amelioration of hepatic steatosis. [32][33][34][35] The role and effects of the persistently increased IL-6 present in a wide variety of disease states, however, remains poorly defined.…”

Section: Discussionsupporting

confidence: 89%

“…14 IL-6 overexpression from a retroviral vector in primates induced marked hepatocyte proliferation in vivo. 15 Administra-tion of an IL-6/soluble IL-6R␣ fusion protein 16 accelerates hepatocyte regeneration, while IL-6 pretreatment protects mice and isolated hepatocytes from Jo-2-mediated cell death. 5 Serum IL-6 is elevated in animal models of and patients with chronic liver diseases.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

et al. 2006

View full text Add to dashboard Cite

Interleukin-6 (IL-6) is an important mediator of liver regeneration and repair that is also elevated in chronic liver diseases, including fatty liver of obesity and cirrhosis. IL-6 has been reported both to delay and accelerate liver regeneration. We examined the effects on liver injury and regeneration of a continuous administration of exogenous IL-6 to mice by injection of an IL-6 -expressing CHO-cell line in athymic nude mice and by osmotic mini-pump delivery of recombinant murine IL-6. Short-term IL-6 administration (1-2 days) accelerated early recovery of liver mass, whereas more long-term administration (5-7 days) markedly impaired liver regeneration. Similarly, short-term IL-6 treatment increased hepatic resistance to the lethal effects of the Fas agonist Jo-2, but on more prolonged IL-6 exposure the Jo-2 resistance vanished. IL-6 administration initially induced expression of the anti-apoptotic proteins Bcl-2 and Bcl-x L , correlating with protection against Fas-mediated cell death. More prolonged IL-6 administration, however, resulted in marked induction of the proapoptotic protein Bax. This result coincided with increased activation of the type II or intrinsic, mitochondrial path to cell death, manifested by increased caspase-9 activation and increased cytochrome c release after Jo-2 exposure. These data demonstrate that IL-6 can function acutely to improve hepatic regeneration and repair, but that more chronic exposure not only abolishes the protective effects of IL-6, but actually sensitizes the liver to injury and death. In conclusion, elevated IL-6 in certain chronic liver diseases contributes to an increased likelihood of liver failure after injury. (HEPATOLOGY 2006;43:474-484.)

show abstract

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

et al. 2006

View full text Add to dashboard Cite

show abstract

“…On this basis, we hypothesized that the MCD diet-induced 'hepatic IL-6 resistance' observed in db/db mice may be attributable to impaired hepatic IL-6 receptor and GP130 mRNA expression, because a previous report showed that treatment with IL-6/soluble IL-6 receptor fusion protein stimulated IL-6-mediated signaling pathway. 26 As shown in Figure 2e, hepatic mRNA expression of the IL-6 receptor and GP130 was confirmed to be significantly downregulated in MCD diet-fed db/db mice, which did not contradict the finding of decreased hepatic STAT3 levels. Initially, we hypothesized that continuous IL-6 stimulation might induce liver injury and fibrosis, and neutralizing the Blockade of IL-6 Receptor in MCD Diet-Fed db/db Mice K Yamaguchi et al IL-6 receptor by treatment with MR16-1 would attenuate liver injury and prevent the development of NASH in MCD diet-fed db/db mice, as in wild-type mice, because previous reports showed that long-term IL-6 exposure induced SOCS3 expression, caused insulin resistance and exacerbated liver injury.…”

Section: Discussionsupporting

confidence: 49%

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

View full text Add to dashboard Cite

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.

show abstract

“…However, while evaluating several indexes of hepatocyte proliferation, Glanemann et al have demonstrated that preoperative steroids administration has no apparent effects on hepatic regeneration. 30 Furthermore, liver regeneration is strictly dependent on cytokine IL-6 33,34 ; it has been suggested that the overproduction of IL-6 inhibits liver regeneration. 35 In the present study, cytokinemia after hepatectomy was clearly attenuated but not completely suppressed by the preoperative administration of methylprednisolone.…”

Section: Discussionmentioning

confidence: 99%

Impact of preoperative steroids administration on ischemia-reperfusion injury and systemic responses in liver surgery: A prospective randomized study

et al. 2006

View full text Add to dashboard Cite

Hepatic injury secondary to warm ischemia-reperfusion (I/R) injury and alterations in haemostatic parameters are often unavoidable events after major hepatic resection. The release of inflammatory mediator is believed to play a significant role in the genesis of these events. It has been suggested that preoperative steroid administration may reduce I/R injury and improve several aspects of the surgical stress response. The aim of this prospective randomized study was to investigate the clinical benefits on I/R injury and systemic responses of preoperatively administered corticosteroids. Seventy-six patients undergoing liver resection were randomized either to a steroid group or to a control group. Patients in the steroid group received preoperatively 500 mg of methylprednisolone. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, coagulation parameters, and inflammatory mediators, interleukin 6 and tumor necrosis factor alpha were compared between the 2 groups. Length of stay, and type and number of complications were recorded as well. Postoperative serum levels of ALT, AST, total bilirubin, and inflammatory cytokines were significantly lower in the steroid than in the control group at postoperative days 1 and 2. Changes in hemostatic parameters were also significantly attenuated in the steroid group. In conclusion, the incidence of postoperative complications in the steroid group tended to be significantly lower than the control group. It is of clinical interest that preoperative steroids administration before major surgery may reduce I/R injury, maintain coagulant/anticoagulant homeostasis, and reduce postoperative complications by modulating the inflammatory response. The human body reacts to surgical stimuli through various systemic responses including the endocrine, metabolic, coagulation, and immune systems. However, extended damage may result in an exaggerated systemic response with an overwhelming activation of immune cells and the release of various mediators of stress. [1][2][3] The systemic reaction to the operation is considered to be equivalent to the systemic inflammation response syndrome, mainly caused by cytokine networks. 4,5 Raised levels of inflammatory cytokines have been related to higher postoperative mortality and morbidity rates. 2,3,6 Therefore, increased attention has evolved toward modulating potentially deleterious inflammatory response to the operation.The anti-inflammatory and immune modulating effects of steroids have been known for decades and have found extensive therapeutic use in a wide range of diseases in which inflammatory responses play major role. 7,8 Several trials have investigated the benefits of administering corticosteroids as a modulator of cytokine response in patients undergoing elective cardiothoracic or gastrointestinal surgery, as well as in cases of septic shock, suggesting that several aspects of the surgical stress responses, organ dysfunction, and postAbbreviations: POD, postoperative day; ALT, alanine aminotr...

show abstract

Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration

Cited by 114 publications

References 30 publications

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

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

Impact of preoperative steroids administration on ischemia-reperfusion injury and systemic responses in liver surgery: A prospective randomized study

Contact Info

Product

Resources

About