Neutralization of interferon‐γ in neonatal SOCS1<sup>−/−</sup> mice prevents fatty degeneration of the liver but not subsequent fatal inflammatory disease

Bullen, Denise V. R.; Darwiche, Rima; Metcalf, Donald; Handman, Emanuela; Alexander, Warren S.

doi:10.1046/j.1365-2567.2001.01294.x

Cited by 40 publications

(32 citation statements)

References 10 publications

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“…Previous studies have shown that T cells from SOCS-1 Ϫ/Ϫ mice display features of activated T cells, such as an increase in cell size and expression of the activation markers CD44, CD69, and CD25 (17,28,29). These features were also typical of T cells from SOCS-1 Ϫ/Ϫ IFN-␥ Ϫ/Ϫ mice.…”

Section: T Cell Activation In Socs-1 ϫ/ϫ Mice Occurs In the Absence Omentioning

confidence: 74%

Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis

Cornish

Davey

Metcalf

et al. 2003

The Journal of Immunology

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Suppressor of cytokine signaling (SOCS)-1 is a member of a family of proteins that negatively regulate cytokine signaling pathways. We have previously established that SOCS-1 is a key regulator of IFN-γ signaling and that IFN-γ is responsible for the complex inflammatory disease that leads to the death of SOCS-1-deficient mice. In this study, we provide evidence that SOCS-1 is also a critical regulator of IFN-γ-independent immunoregulatory factors. Mice lacking both SOCS-1 and IFN-γ, although outwardly healthy, have clear abnormalities in their immune system, including a reduced ratio of CD4:CD8 T cells in lymphoid tissues and increased expression of T cell activation markers. To examine the contribution of TCR Ag specificity to these immune defects, we have generated two lines of SOCS-1-deficient mice expressing a transgenic TCR specific for an exogenous Ag, OVA (OT-I and OT-II). Although TCR transgenic SOCS-1−/− mice have a longer lifespan than nontransgenic SOCS-1−/− mice, they still die as young adults with inflammatory disease and the TCR transgenic SOCS-1−/− T cells appear activated despite the absence of OVA. This suggests that both Ag-dependent and -independent mechanisms contribute to the disease in SOCS-1-deficient mice. Thus, SOCS-1 is a critical regulator of T cell activation and homeostasis, and its influence extends beyond regulating IFN-γ signaling.

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Section: T Cell Activation In Socs-1 ϫ/ϫ Mice Occurs In the Absence Omentioning

confidence: 74%

Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis

Cornish

Davey

Metcalf

et al. 2003

The Journal of Immunology

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“…It suggested that the hypersensitivity of the mice to IFN-γ caused that inflammatory syndrome. SOCS-1 was a key negative regulator of gamma interferon action in vivo [29] and can inhibited the extent of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance

Zhao¹,

Qing-xian²,

Peng³

et al. 2008

WJG

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“…These studies support the concept that the protective effect of SAMe and PTCA (GSH prodrugs) are mediated by prompting the biosynthesis of hepatic GSH. Finally orally administered SAMe [20] as well as PTCA [33] have been reported to be well tolerated and safe.…”

Section: Discussionmentioning

confidence: 99%

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Chen

et al. 2006

J Biochem & Molecular Tox

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Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno-ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine-choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2) S-adenosylmethionine (SAMe), or (3) 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). Results: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups ( p < 0.01). Serum transaminases were considerably elevated (AST: 5.8-fold; ALT: 3.22-fold) in MCD rats. However, administration of GSH-enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT-PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen-␣1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL-1␤, IL-6, TNF-␣, and TGF-␤) in the livers of rats fed MCD. GSH-enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients. C

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Neutralization of interferon‐γ in neonatal SOCS1^−/− mice prevents fatty degeneration of the liver but not subsequent fatal inflammatory disease

Cited by 40 publications

References 10 publications

Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis

Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis

Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

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Neutralization of interferon‐γ in neonatal SOCS1−/− mice prevents fatty degeneration of the liver but not subsequent fatal inflammatory disease

Cited by 40 publications

References 10 publications

Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis

Suppressor of Cytokine Signaling-1 Has IFN-γ-Independent Actions in T Cell Homeostasis

Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Contact Info

Product

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Neutralization of interferon‐γ in neonatal SOCS1^−/− mice prevents fatty degeneration of the liver but not subsequent fatal inflammatory disease