Cytokine Expression in Three Mouse Models of Experimental Hepatitis

Sass, Gabriele; Heinlein, Sonja; Agli, Andrea; Bang, Renate; Schumann, Johann; Tiegs, Gisa

doi:10.1006/cyto.2002.1948

Cited by 188 publications

(155 citation statements)

References 22 publications

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“…Even when cellular integrity is maintained, hepatocyte HMGB1 expression increases quickly after noxious stimuli. 17,34 In this study, immunohistochemistry revealed HMGB1 expression predominantly in hepatocytes located close to the central veins, that is, in areas most susceptible to ischemic injury. Furthermore, hepatocyte HMGB1 expression correlated with HMGB1 levels in the caval effluent.…”

Section: Discussionmentioning

confidence: 52%

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

et al. 2008

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High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor ␣ (TNF-␣), and interleukin-6 (IL-6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80-371) ng/mL] than in portal venous blood [0 (0-3) ng/mL, P Ͻ 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF-␣ or IL-6 levels. HMGB1 expression was up-regulated in biopsies taken after reperfusion (P ϭ 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r ϭ 0.497, P ϭ 0.03) and peak postoperative alanine aminotransferase levels (r ϭ 0.588, P ϭ 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14: 1517Transpl 14: -1525Transpl 14: , 2008

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Section: Discussionmentioning

confidence: 52%

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

et al. 2008

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“…The role of RIPK3 in Con A-induced hepatitis remains to be determined. The required acidic conditions during Con A-induced hepatitis or TRAIL-mediated necroptosis could be generated by the inflamed liver environment, 38 which could lead to acidification of the extracellular environment. 10 Necrotic death is associated with diverse pathological conditions, including myocardial infarction, cerebral ischemia, acute organ failure and infection.…”

Section: Discussionmentioning

confidence: 99%

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

et al. 2012

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Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAILinduced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.

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“…Administration of Con A immediately activates several immunocytes and induces production of various cytokines (32). Especially IFN-␥ and IL-4 play a key role in the liver injury.…”

Section: Discussionmentioning

confidence: 99%

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

Yamanaka

Hamano

Miyazaki

et al. 2004

The Journal of Immunology

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Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-γ and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-γ and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.

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Cytokine Expression in Three Mouse Models of Experimental Hepatitis

Cited by 188 publications

References 22 publications

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

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