Suppressors of cytokine signaling and immunity

Kubo, Masato; Hanada, Toshikatsu; Yoshimura, Akihiko

doi:10.1038/ni1012

Cited by 570 publications

(504 citation statements)

References 78 publications

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“…SOCS1 is induced by various cytokines including interferon (IFN)-g, interleukin-4, TNF-a, as well as growth hormones, and downregulates the signals induced by these cytokines in a feedback loop. However, recent studies have indicated that SOCS1 plays diverse roles in cell growth, differentiation, innate immunity, inflammation and apoptosis (Kinjyo et al, 2002;Kubo et al, 2003;He et al, 2006). For example, SOCS1 may suppress the development and/or progression of hepatocellular carcinoma and hematopoietic malignancies (Yoshida et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

Hur

2009

Oncogene

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Suppressors of cytokine signaling (SOCS) are negative regulators of cytokine-induced signal transduction, which play multiple roles in cell growth, differentiation and apoptosis. In this study, the regulatory role of SOCS in oxidative stress-induced apoptosis was investigated. In Jurkat T cells and mouse splenocytes, we have found that SOCS1 is induced in response to tumor necrosis factor-a or H 2 O 2 , concomitant with the activation of Jaks which act as important mediators of reactive oxygen species (ROS)-induced apoptosis upstream of p38 mitogenactivated protein kinase. Using SOCS1 overexpressing or knockdown Jurkat T-cell systems we clearly demonstrate that, SOCS1 inhibits the ROS-mediated apoptosis. The antiapoptotic action of SOCS1 was exerted not only by suppressing Jaks, but also by sustaining protein tyrosine phosphatase (PTP) activities. Notably, SOCS1-transduced cells displayed increase in thioredoxin levels and decrease in ROS generation induced by oxidative stress. In addition, the Jak-inhibiting and PTP-sustaining effect of SOCS1 was significantly reduced on thioredoxin ablation. Moreover, coimmunoprecipitation data revealed molecular interaction of SHP1 or CD45 with thioredoxin, which was promoted in SOCS1-transfected cells. Together, our data strongly suggest that both the protection of PTPs by thioredoxin from ROS attack and the attenuation of Jaks account for the antiapoptotic function of SOCS1 in immune cells under oxidative stress.

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Section: Introductionmentioning

confidence: 99%

“…SOCS1 has been shown to regulate the sensitivity of pancreatic islet cells toward the TNF-a-induced cytotoxicity mediated by p38 MAPK (Chong et al, 2002). In addition, SOCS1 may act as a modulator of apoptosis to ensure controlled survival and apoptosis during pregnancy and involution, respectively (Kubo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

Hur

2009

Oncogene

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“…SOCS4-7 are each composed of a long N-terminal region of over 200 amino acids, whereas CIS and SOCS1-3 have a short N-terminal region of less than 50 amino acids [4,5]. SOCS proteins with a short N-terminal domain have been extensively studied, and are disease-associated [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Increased cytoplasmic levels of CIS, SOCS1, SOCS2, or SOCS3 are required for nuclear translocation

et al. 2008

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We investigated the cellular localization of ectopically-expressed CIS, SOCS1, SOCS2 and SOCS3 proteins. We found that SOCS proteins localize to the nucleus where they reduce Stat3 proteins and that the presence of proteasome inhibitors increased SOCS nuclear localization. Our results indicate that increased nuclear localization resulted from increased levels of SOCS proteins in the cytoplasm. Finally, we demonstrate that the same effect occurs with endogenously-expressed SOCS proteins. These observations suggest that increased cytoplasmic levels of proteins in the SOCS family are regulated through nuclear translocation.

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“…One molecule that is important for the induction of tolerance and CD4 + regulatory T cells is the suppressor of cytokine signalling 3 (SOCS3), 21 an antagonist of MF activation, which can be down-regulated by IL-15 in IL-15MF and in IL-15 tg MF (Fig. 4a).…”

Section: Long-term Il-15 Exposure Suppresses Negative Regulators Of Mmentioning

confidence: 99%

Interleukin‐15 stimulates macrophages to activate CD4⁺ T cells: a role in the pathogenesis of rheumatoid arthritis?

et al. 2008

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Interleukin-15 stimulates macrophages to activate CD4 + T cells: a role in the pathogenesis of rheumatoid arthritis?Introduction ) is expressed in a wide variety of cell types, including fibroblasts, keratinocytes, epithelial cells, osteoclasts and activated monocytes. It is also produced by haematopoietic progenitors and bone marrow stromal cells 1 and by differentiated antigen-presenting cells and phagocytes, such as dendritic cells (DCs) and macrophages (MF). 2 We have reported that interaction between IL-15 and the IL-15 receptor a (IL-15Ra) in DCs is critical for maturation and antigen presentation to T cells. 3,4 Studies with IL-15Ra )/) and IL-15 )/) mice show that IL-15 is an essential cytokine for the development and survival of natural killer (NK) cells, NK T cells, and memory and activated CD8 + T cells. Interleukin-15 is a potent proinflammatory cytokine that induces, for example, tumour necrosis factor-a (TNF-a), IL-1b and inflammatory chemokines. It inhibits self-tolerance and facilitates the maintenance of memory T-cell survival, including that of self-directed cells. Deregulated IL-15 expression has been reported in patients with an array of inflammatory autoimmune diseases. SummaryInterleukin-15 (IL-15) is a proinflammatory cytokine that is overexpressed in rheumatoid arthritis (RA), a disease characterized by activation of monocytes/macrophages (MF), and by expansion of autoreactive CD4 + T cells. We hypothesized that IL-15 plays a major role for this expansion of CD4 + T cells and modulates the phenotype of monocytes/MF and their interaction with CD4 + T cells. Here, we show that IL-15 enhances the proliferation of CD4 + T cells from patients with RA in peripheral blood mononuclear cell cocultures. To further dissect the underlying mechanisms, we employed MF from IL-15 )/) or IL-15 transgenic mice. These were induced to differentiate or were stimulated with IL-15. Here we show that addition of IL-15 during differentiation of MF (into 'IL-15MF') and overexpression of IL-15 by MF from IL-15 tg mice leads to increased levels of major histocompatibility complex class II expression. This resulted in enhanced stimulation of antigen-specific CD4 + T cells in vitro and was accompanied by reduced messenger RNA expression in MF for immunosuppressive SOCS3. The proliferation rates of IL-15MF and IL-15 tg MF were high, which was reflected by increased p27 Kip1 and reduced p21 Waf1 levels. In view of high serum and synovial levels of IL-15 in patients with RA, our data suggest the possibility that this excess IL-15 in RA may stimulate monocytes/MF to activate the characteristic autoreactive CD4 + T cells in RA.

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Suppressors of cytokine signaling and immunity

Cited by 570 publications

References 78 publications

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

Increased cytoplasmic levels of CIS, SOCS1, SOCS2, or SOCS3 are required for nuclear translocation

Interleukin‐15 stimulates macrophages to activate CD4⁺ T cells: a role in the pathogenesis of rheumatoid arthritis?

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Suppressors of cytokine signaling and immunity

Cited by 570 publications

References 78 publications

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

Increased cytoplasmic levels of CIS, SOCS1, SOCS2, or SOCS3 are required for nuclear translocation

Interleukin‐15 stimulates macrophages to activate CD4+ T cells: a role in the pathogenesis of rheumatoid arthritis?

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Interleukin‐15 stimulates macrophages to activate CD4⁺ T cells: a role in the pathogenesis of rheumatoid arthritis?