Importance of Kupffer Cells for T-Cell-Dependent Liver Injury in Mice

Schumann, Johann; Wolf, Dominik; Pahl, Andreas; Brune, Kay; Papadopoulos, Thomas; Rooijen, Nico van; Tiegs, Gisa

doi:10.1016/s0002-9440(10)64804-3

Cited by 266 publications

(241 citation statements)

References 56 publications

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“…1). Although NKT cells are the primary source of IFN-␥ and IL-4, and presumably IL-5 (19), cytokines such as TNF-␣, IL-1, and IL-6 are probably produced by Kupffer cells in the liver (8) in response to IFN-␥ and IL-4 produced by NKT cells. As macrophages are positive for the expression of WSX-1 by RT-PCR (22), it is possible that WSX-1-deficient macrophages (Kupffer cells) are also more sensitive to stimulation and are prone to overproduction of inflammatory cytokines.…”

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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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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“…4,6 To elucidate mechanisms leading to iNOS expression in this model, we first pretreated mice with neutralizing antibodies to TNF or IFN-␥. Although iNOS expression was significantly reduced in both cases, only pretreatment with a combination of both antibodies completely abolished con A-induced iNOS expression.…”

Section: Discussionmentioning

confidence: 99%

“…TNF and IFN-␥ are crucially responsible for induction of liver injury after administration of con A, 4,6 and both cytokines induce iNOS in vitro. 10,12 To assess the importance of TNF and IFN-␥ for iNOS induction in vivo following con A injection, mice were pretreated with neutralizing antibodies to IFN-␥ and/or TNF.…”

Section: Tnf and Ifn-␥ Are Equally Involved In Conmentioning

confidence: 99%

“…2,3 Con A-induced liver injury is crucially dependent on IFN-␥ and Kupffer cell-derived TNF, because Kupffer cell depletion as well as pretreatment with polyclonal anti-TNF or anti-IFN-␥ antibodies protected mice from con A-induced hepatic damage. [4][5][6] It has also been shown that TNF contributes to con A-induced hepatitis by signaling through both of its receptors (i.e., the 55-kd TNF receptor [TNFR] 1 and the 75-kd TNFR2), because knockout mice for each receptor are protected. 7 Although TNFR1 is well known as cell death receptor on hepatocytes, 8,9 the role of TNFR2 is less clear.…”

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confidence: 99%

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In vivo regulation of inducible NO synthase in immune-mediated liver injury in mice

Koerber

Sass

Kiemer³

et al. 2002

Hepatology

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Inducible nitric oxide synthase (iNOS) has been shown to play an important role in the development of liver injury. iNOS deficiency protects mice from hemorrhage/resuscitation as well as from cytokine-mediated liver injury, for example, after administration of concanavalin A (con A). Here we investigated the in vivo effects of tumor necrosis factor (TNF)-␣ and/or interferon (IFN)-␥, two mediators of con A-induced liver injury, the TNF receptor (TNFR) usage leading to iNOS expression, and its connection with nuclear factor B (NF-B) activation. In conclusion, iNOS expression in vivo is dependent on both TNF-␣ and IFN-␥. Although con A-induced liver injury depends on both TNFR1 and TNFR2, TNF-dependent iNOS expression is mediated exclusively by TNFR1 and requires NF-B activation. (HEPATOLOGY

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“…For determination of intrahepatic TNF concentrations, livers were prepared as described previously. 16 Liver lysates were adjusted to equal protein concentrations and analyzed for murine TNF with the Quantikine M Kit (BioRad, Munich, Germany).…”

Section: Egradation Of Heme By Heme Oxygenases (Hos)mentioning

confidence: 99%

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

et al. 2004

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Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of results in the production of carbon monoxide (CO), free iron, and biliverdin (BV). HO-1, in contrast to the second isoform HO-2, is inducible by various stimuli. 1,2 To investigate HO effects in vitro as well as in vivo, HO-1 can be induced by application of cobalt-protoporphyrin-IX (CoPP), for example, while tin-protoporphyrin-IX (SnPP) suppresses HO activity. 3,4 In the liver, administration of CoPP to mice results in HO-1 expression in hepatocytes as well as in Kupffer cells. 5 In vivo, HO-1 induction has been shown previously to protect mice from apoptotic liver damage 5 and to protect rats from liver graft rejection as well as from ischemia/reperfusion injury. 6 -8 To investigate mechanisms of cytokine-dependent liver injury, mice can be sensitized with the hepatocytespecific transcriptional inhibitor D-galactosamine (GalN) in combination with the macrophage activator lipopolysaccharide (LPS). 9 In this GalN/LPS model, mice develop severe liver injury, which is dependent on tumor necrosis factor (TNF) 10,11 and interferon ␥ (IFN-␥) 12 induction, while interleukin (IL) 10 prevents injury. 13 In the present study we show that HO-1, induced by CoPP, protects mice from GalN/LPS-induced liver injury, prolongs survival, and reduces cytokine expression. Protection from liver damage could also be achieved by pretreatment with the HO products CO and BV, but not by ferritin. Prolongation of survival and cytokine reduction was only detectable in mice pretreated with a combination of both hepatoprotective products CO and BV. Materials and MethodsAnimals. BALB/c-mice (6-8 weeks old; weight range, 18-22 g) were obtained from the animal facilities of the

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Importance of Kupffer Cells for T-Cell-Dependent Liver Injury in Mice

Cited by 266 publications

References 56 publications

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

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

In vivo regulation of inducible NO synthase in immune-mediated liver injury in mice

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

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