Age-Associated Augmentation of the Synthetic Ligand- Mediated Function of Mouse NK1.1 Ag+ T Cells: Their Cytokine Production and Hepatotoxicity In Vivo and In Vitro

Inui, Takuo; Nakagawa, Ryusuke; Ohkura, Shuri; Habu, Yoshiko; Koike, Yuji; Motoki, Kazuhiro; Kuranaga, Noritsugu; Fukasawa, Masashi; Shinomiya, Nariyoshi; Seki, Shu

doi:10.4049/jimmunol.169.11.6127

Cited by 54 publications

(70 citation statements)

References 37 publications

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“…11). However, in this work, we could clearly show that IFN-␥ is not pivotal for ␣-GalCer-induced hepatotoxicity, which is consistent with recently published results (32). Unexpectedly, IFN-␥ neutralization even aggravated liver injury in this model.…”

Section: Discussionsupporting

confidence: 93%

“…Because both cytokines are induced upon ␣-GalCer treatment, with the time course of ␣-GalCer-induced IFN-␥ expression resembling that of ALT release, we analyzed the effect of neutralizing Abs against these cytokines in the ␣-GalCer model. Surprisingly, neutralization of IFN-␥ not only failed to block ␣-GalCer-mediated hepatic injury, as had already been previously described (32), but even caused an increased ALT release (Fig. 3A).…”

Section: Relevance Of ␣-Galcer-induced Cytokines For Liver Injurysupporting

confidence: 82%

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α-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-α but Independent of Kupffer Cells

Biburger

Tiegs

2005

The Journal of Immunology

150

223

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NKT cells expressing phenotypic markers of both T and NK cells seem to be pivotal in murine models of immune-mediated liver injury, e.g., in Con A-induced hepatitis. Also α-galactosylceramide (α-GalCer), a specific ligand for invariant Vα14 NKT cells, induces hepatic injury. To improve the comprehension of NKT-cell mediated liver injury, we investigated concomitants and prerequisites of α-GalCer-induced hepatitis in mice. Liver injury induced by α-GalCer injection into C57BL/6 mice was accompanied by intrahepatic caspase-3 activity but appeared independent thereof. α-GalCer injection also induces pronounced cytokine responses, including TNF-α, IFN-γ, IL-2, IL-4, and IL-6. We provide a detailed time course for the expression of these cytokines, both in liver and plasma. Cytokine neutralization revealed that, unlike Con A-induced hepatitis, IFN-γ is not only dispensable for α-GalCer-induced hepatotoxicity but even appears to exert protective effects. In contrast, TNF-α was clearly identified as an important mediator for hepatic injury in this model that increased Fas ligand expression on NKT cells. Whereas intrahepatic Kupffer cells are known as a pivotal source for TNF-α in Con A-induced hepatitis, they were nonessential for α-GalCer-mediated hepatotoxicity. In α-GalCer-treated mice, TNF-α was produced by intrahepatic lymphocytes, in particular NKT cells. BALB/c mice were significantly less susceptible to α-GalCer-induced liver injury than C57BL/6 mice, in particular upon pretreatment with d-galactosamine, a hepatocyte-specific sensitizer to TNF-α-mediated injury. Finally, we demonstrate resemblance of murine α-GalCer-induced hepatitis to human autoimmune-like liver disorders. The particular features of this model compared with other immune-mediated hepatitis models may enhance comprehension of basic mechanisms in the etiopathogenesis of NKT cell-comprising liver disorders.

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Section: Discussionsupporting

confidence: 93%

Section: Relevance Of ␣-Galcer-induced Cytokines For Liver Injurysupporting

confidence: 82%

α-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-α but Independent of Kupffer Cells

Biburger

Tiegs

2005

The Journal of Immunology

150

223

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“…In general, however, both the quantitative and functional deficiency of NKT cells (when tested) in these studies was not as profound as that found in this population of MDS patients. The impact of age or sex on NKT function in humans is not clear, although an increase in NKT function has been suggested in older mice (Inui et al, 2002). Recent studies showed that NKT function was preserved in patients with monoclonal gammopathy , who had a similar age distribution to the MDS patients in the present study.…”

Section: Resultssupporting

confidence: 48%

Severe and selective deficiency of interferon‐γ‐producing invariant natural killer T cells in patients with myelodysplastic syndromes

et al. 2003

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Summary. Here we show that patients with myelodysplastic syndromes (MDS) have a severe deficiency of glycolipid reactive Va24 + /Vb11 + natural killer T (NKT) cells, but not NK cells or CD4 + or CD8 + T cells. Neither the blood nor marrow of MDS patients had detectable interferonc-producing NKT cells in response to the NKT ligand, a-galactosyl ceramide, although influenza-virus-specific effector T-cell function was preserved. This severe and selective deficiency of an important immune regulatory cell may contribute to the pathogenesis of MDS.

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“…1B). Previously, we found that NKT cell activities after a-GalCer stimulation increase age-dependently, while those after anti-CD3 Ab stimulation are independent of age [25]. Obviously a-GalCer stimulates mouse NKT cells in a CD1d-dependent manner [26].…”

Section: Discussionmentioning

confidence: 78%

IL‐18 time‐dependently modulates Th1/Th2 cytokine production by ligand‐activated NKT cells

et al. 2007

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While IL-18 synergizes with IL-12 to induce a Th1 immune response, it also promotes a Th2 response. Here we investigate the modulatory role of IL-18 on the Th1/Th2 cytokine response. The injection of a-galactosylceramide (a-GalCer), a ligand for NKT cells, elevated mouse serum levels of both IFN-c and IL-4. When the mice were treated 2 h before a-GalCer challenge with IL-18, IFN-c production but not IL-4 production was remarkably up-regulated. In contrast, pretreatment with IL-18 6 h before the challenge enhanced IL-4 production. However, this IL-18-enhanced IL-4 production was not elicited in mice injected with anti-CD3 Ab. Liver mononuclear cells (MNC) produced a similar cytokine production pattern when MNC from mice treated with IL-18 either 2 h or 6 h before challenge were stimulated with a-GalCer in vitro. Expression of SOCS1 and SOCS3 was notably up-regulated in the liver MNC from mice pretreated 6 h before with IL-18; in particular, SOCS3 expression was confined to the liver NKT cells. Inhibition of SOCS3 by RNA interference up-regulated the phosphorylation of STAT3 and suppressed in vitro IL-4 production by IL-18-primed liver MNC stimulated with a-GalCer, but it did not affect IFN-c production. These results suggest that IL-18 timedependently modulates Th1/Th2 cytokine production in ligand-activated NKT cells by regulating/inducing SOCS3 expression.

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Age-Associated Augmentation of the Synthetic Ligand- Mediated Function of Mouse NK1.1 Ag+ T Cells: Their Cytokine Production and Hepatotoxicity In Vivo and In Vitro

Cited by 54 publications

References 37 publications

α-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-α but Independent of Kupffer Cells

α-Galactosylceramide-Induced Liver Injury in Mice Is Mediated by TNF-α but Independent of Kupffer Cells

Severe and selective deficiency of interferon‐γ‐producing invariant natural killer T cells in patients with myelodysplastic syndromes

IL‐18 time‐dependently modulates Th1/Th2 cytokine production by ligand‐activated NKT cells

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