SOCS-1/SSI-1-Deficient NKT Cells Participate in Severe Hepatitis through Dysregulated Cross-Talk Inhibition of IFN-γ and IL-4 Signaling In Vivo

Naka, Tetsuji; Tsutsui, Hiroko; Fujimoto, Minoru; Kawazoe, Yoshinori; Kohzaki, Hidetsugu; Morita, Yoshiaki; Nakagawa, Reiko; Narazaki, Masashi; Adachi, Keishi; Yoshimoto, Tomohiro; Nakanishi, Kenji; Kishimoto, Tadamitsu

doi:10.1016/s1074-7613(01)00132-7

Cited by 176 publications

(130 citation statements)

References 46 publications

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“…This finding is consistent with previous studies that have found SOCS-1 to regulate IL-4, both in vitro and in vivo (3,(41)(42)(43). Although not as potent as IL-2 for inducing proliferation, IL-4 strongly sustained the survival of SOCS-1 Ϫ/Ϫ IFN␥ Ϫ/Ϫ T cells.…”

Section: Socs-1 Regulates ␥C-dependent Cytokine Signalingsupporting

confidence: 93%

Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells

Cornish

Chong

Davey

et al. 2003

Journal of Biological Chemistry

114

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Section: Socs-1 Regulates ␥C-dependent Cytokine Signalingsupporting

confidence: 93%

Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells

Cornish

Chong

Davey

et al. 2003

Journal of Biological Chemistry

114

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“…Methylation studies by both MSP analysis and bisulphite sequencing confirmed that CpG island of SOCS-1 was methylated in AGS cells but not other cell lines. Although KATO III did not express IL-6, the high level of SOCS-1 detected may act as a negative regulation for other cytokines expressed in this cell line (Haque et al, 2000;Cottet et al, 2001;Naka et al, 2001;Eyles et al, 2002).…”

Section: Discussionmentioning

confidence: 70%

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Chan

Leung

et al. 2004

Br J Cancer

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The interleukin-mediated Janus kinase (JAK)/STAT pathway plays a crucial role in carcinogenesis. Recently, increased STAT3 activity was found in hepatocellular carcinoma and multiple myeloma in which there was silencing of SOCS-1 (suppressor of cytokine signalling-1) by gene promoter hypermethylation. We investigated the expression level of interleukin-6 (IL-6) and SOCS-1 in gastric cancer cell lines. Expression of SOCS-1 correlated with IL-6 level in most of the cell lines, except for AGS cells in which SOCS-1 was absent despite a high level of IL-6 production. Methylation analysis by methylation-specific polymerase chain reaction and bisulphite sequencing revealed that CpG island of SOCS-1 was densely methylated in AGS cells. Demethylation treatment by 5 0 azadeoxycytidine restored SOCS-1 expression and also suppressed constitutive STAT3 phosphorylation in AGS cells. Moreover, methylation of SOCS-1 was detected in 27.5% (11 of 40) of primary gastric tumours samples, 10% (one of 10) of adjacent noncancer tissues but not in any (zero of nine) normal gastric mucosa. Methylation of SOCS-1 also correlated with the loss of mRNA expression in some primary gastric cancers. In conclusion, this is the first report to demonstrate that hypermethylation of SOCS-1 led to gene silencing in gastric cancer cell line and primary tumour samples. Downregulation of SOCS-1 cooperates with IL-6 in the activation of JAK/STAT pathway in gastric cancer.

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“…IFN-␥ is mainly produced by activated T lymphocytes, NK, and NKT cells (38,39). Recent studies have shown that lymphocytes are required for the manifestation of the profound SOCS-1 Ϫ/Ϫ phenotype, and that SOCS-1 Ϫ/Ϫ NKT cells can induce the liver disease characteristic of these mice (17,40). Furthermore, T cells appear abnormally activated in SOCS-1 Ϫ/Ϫ mice, suggesting the possibility that these activated cells contribute to the increased IFN-␥ production (17).…”

Section: Discussionmentioning

confidence: 99%

“…Cytokines that signal through the common ␥-chain are thought to be important both for maintaining survival of naive cells and for stimulating homeostatic proliferation (44,49). Several reports have described a role for SOCS-1 in the regulation of this family of cytokines (13,21,40). In the absence of SOCS-1, homeostatic signals may not be regulated appropriately.…”

Section: Discussionmentioning

confidence: 99%

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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SOCS-1/SSI-1-Deficient NKT Cells Participate in Severe Hepatitis through Dysregulated Cross-Talk Inhibition of IFN-γ and IL-4 Signaling In Vivo

Cited by 176 publications

References 46 publications

Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells

Suppressor of Cytokine Signaling-1 Regulates Signaling in Response to Interleukin-2 and Other γc-dependent Cytokines in Peripheral T Cells

Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

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

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