Suppressors of cytokine signaling in health and disease

Tan, Jane C.; Rabkin, Ralph

doi:10.1007/s00467-004-1766-8

Cited by 73 publications

(51 citation statements)

References 80 publications

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“…such as STAT1, STAT3, and STAT5, are activated in numerous cell types by a wide variety of cytokines and are involved in mediating general signals for cell growth and survival. Others, including STAT2, STAT4, and STAT6, are more restricted in their expression, are activated in response to a small number of cytokines and play a distinct role in IFN-γ signaling and the development of T-cells [21,22]. STAT6 activation is known to be closely related to the inhibition of cell growth and the induction of apoptosis in human cancer cells [23], normal hepatocytes [24], and endothelial cells [25].…”

Section: Discussionmentioning

confidence: 99%

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Kim

Lee

et al. 2011

Cell Res

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We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4 −/− , but not in STAT6 −/− mice. Moreover, the expression levels of the protein and mRNA of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4 −/− , but not STAT6 −/− mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6 −/− mice were intact after treatment with cisplatin, whereas those from WT and STAT4 −/− mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells, and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Rα1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.

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Section: Discussionmentioning

confidence: 99%

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Kim

Lee

et al. 2011

Cell Res

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“…Activation of JAK/STAT pathway leads to induction of suppressors of cytokines signaling molecules (SOCSs), in particular SOCS3 (Tan and Rabkin, 2005). The functional role of SOCS3 is to act as negative feedback inhibitor of the JAK/STAT pathway by avoiding STAT3 phosphorylation (Krebs and Hilton, 2001;Himpe and Kooijman, 2009).…”

Section: Galectin-3 Deficiency Leads To Overexpression Of Il-6 and Inmentioning

confidence: 99%

Galectin-3 Is Required for Resident Microglia Activation and Proliferation in Response to Ischemic Injury

Lalancette–Hébert¹,

Swarup²,

Beaulieu³

et al. 2012

Journal of Neuroscience

234

247

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Growing evidence suggests that galectin-3 is involved in fine tuning of the inflammatory responses at the periphery, however, its role in injured brain is far less clear. Our previous work demonstrated upregulation and coexpression of galectin-3 and IGF-1 in a subset of activated/proliferating microglial cells after stroke. Here, we tested the hypothesis that galectin-3 plays a pivotal role in mediating injury-induced microglial activation and proliferation. By using a galectin-3 knock-out mouse (Gal-3KO), we demonstrated that targeted disruption of the galectin-3 gene significantly alters microglia activation and induces ϳ4-fold decrease in microglia proliferation. Defective microglia activation/proliferation was further associated with significant increase in the size of ischemic lesion, ϳ2-fold increase in the number of apoptotic neurons, and a marked deregulation of the IGF-1 levels. Next, our results revealed that contrary to WT cells, the Gal3-KO microglia failed to proliferate in response to IGF-1. Moreover, the IGF-1-mediated mitogenic microglia response was reduced by N-glycosylation inhibitor tunicamycine while coimmunoprecipitation experiments revealed galectin-3 binding to IGFreceptor 1 (R1), thus suggesting that interaction of galectin-3 with the N-linked glycans of receptors for growth factors is involved in IGF-R1 signaling. While the canonical IGF-1 signaling pathways were not affected, we observed an overexpression of IL-6 and SOCS3, suggesting an overactivation of JAK/STAT3, a shared signaling pathway for IGF-1/IL-6. Together, our findings suggest that galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury.

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“…They mediate their action by either interacting with cytokine receptors or directly binding to phosphorylated tyrosine residues of Jaks (18,19). Studies with SOCS1-or SOCS3-deficient mice indicate that SOCS1 is primarily a negative regulator of IFN signaling (20,21), whereas SOCS3 is primarily a negative regulator of interleukin-6 signaling (22).…”

Section: Introductionmentioning

confidence: 99%

SOCS1 Silencing Enhances Antitumor Activity of Type I IFNs by Regulating Apoptosis in Neuroendocrine Tumor Cells

et al. 2007

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IFN-A is commonly used for biotherapy of neuroendocrine carcinomas. However, its antitumor efficacy is often limited due to IFN resistance. In this study, we evaluate the role of suppressor of cytokine signaling protein 1 (SOCS1) in modulating the effects of type I IFNs (IFN-A and IFN-B) in human neuroendocrine BON1 and CM tumor cells. In both cell lines, type I IFNs activated signal transducers and activators of transcription (STAT) and significantly decreased cell viability. However, the effects of IFN-B were significantly more pronounced than those of IFN-A and involved the induction of the intrinsic apoptotic pathway as shown by cleavage of caspase-8, Bid, and caspase-9. Stable overexpression of SOCS1 completely abolished the apoptotic effects of both type I IFNs. In contrast, small interfering RNA (siRNA)-mediated silencing of SOCS1 resulted in strongly enhanced type I IFN signaling as shown by increased and prolonged STAT phosphorylation and stronger induction of apoptosis. Silencing of SOCS1 was associated with down-regulation of basal Bcl-2 and Bcl-xL and up-regulation of basal Bak and Bax, suggesting that reduced SOCS1 expression might lower the threshold of susceptibility to type I IFN-mediated apoptosis by decreasing the ratio of antiapoptotic to proapoptotic molecules. In summary, our results indicate an important role of SOCS1 in IFN resistance of neuroendocrine tumor cells, mediated through negative regulation of type I IFN-induced Jak/STAT signaling. Knocking down SOCS1 by siRNA is a promising new approach to enhance the therapeutic potency of type I IFNs in neuroendocrine tumors. [Cancer Res 2007;67(10):5025-32]

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Suppressors of cytokine signaling in health and disease

Cited by 73 publications

References 80 publications

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Galectin-3 Is Required for Resident Microglia Activation and Proliferation in Response to Ischemic Injury

SOCS1 Silencing Enhances Antitumor Activity of Type I IFNs by Regulating Apoptosis in Neuroendocrine Tumor Cells

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