SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-α signaling

Chhabra, Jasmeet Kaur; Chattopadhyay, Brajadulal; Paul, Bhola Nath

doi:10.1038/cmi.2013.36

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…STAT3 is activated by IL-6 trans-signaling and involved in pancreatic damage in AP ( 9 , 10 ). SOCS3 functions to negatively regulate NF-κB and STAT3 signaling pathways ( 25 ). In addition, it is essential for M1 macrophage polarization and thus modulating M1 macrophage-mediated inflammatory responses ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

et al. 2018

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Acute pancreatitis (AP), a common abdominal inflammatory disorder, is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. Although the mechanism remains to be fully understood, inflammation is the main cause of pancreatic damage in AP. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits anti-inflammatory and anti-apoptotic properties in vitro. However, its potential beneficial effect in AP has not been demonstrated. This study aimed to investigate the effects and underlying mechanisms of DSC in experimental AP in mice. We found that DSC suppressed inflammatory responses in AP by inhibiting the activation of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome. Furthermore, treatment with DSC modulated the infiltration of neutrophils and the phenotypes of macrophages in mice induced with AP. Interestingly, we found that the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and its regulated antioxidant enzyme heme oxygenase-1 (HO-1), which modulate inflammatory activities, was significantly increased in DSC-treated groups. Together, our findings demonstrate that DSC alleviates pancreatic inflammation and damage in AP by inhibiting the activation of NF-κB, STAT3, and NLRP3 inflammasome and modulating immune cell responses.

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Section: Discussionmentioning

confidence: 99%

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

et al. 2018

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“…Leptin binding to its receptor leads to activation of multiple intracellular pathways including the Janus kinase-2 (JAK2)-STAT3, mitogen-activated protein kinase (MAPK), nuclear factor (NF)-kB and PI3K/Akt pathways, all of which have been shown to be involved in the leptin-induced production of proinflammatory factors by chondrocytes [ 11 – 15 , 18 , 19 ]. SOCS-3 has been shown to inhibit not only the STAT3 pathway, but also the extracellular signal-related kinase (Erk)1/2 and NF-kB pathways [ 34 , 35 ], providing a possible mechanistic explanation for how leptin-induced responses could be modulated by SOCS-3 in chondrocytes. Interestingly Pallu et al report higher leptin-induced activation of STAT3 in chondrocytes from obese than from non-obese patients [ 17 ], which could be a consequence of decreased SOCS-3 expression, and may explain the differential leptin responsiveness in obese individuals observed in their study.…”

Section: Discussionmentioning

confidence: 99%

Catabolic and proinflammatory effects of leptin in chondrocytes are regulated by suppressor of cytokine signaling-3

et al. 2016

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BackgroundPrevious studies provide evidence that adipokine leptin increases production of catabolic and proinflammatory factors in chondrocytes and serves as a link between obesity and osteoarthritis (OA). However, the magnitude of the response to leptin treatment varies greatly between chondrocytes from different donor patients. In the present study, we investigated the regulatory role of suppressor of cytokine signaling-3 (SOCS-3) in the leptin-induced responses in OA cartilage.MethodsCartilage and synovial fluid samples from 97 patients with OA undergoing knee replacement surgery were collected. Cartilage samples were cultured with leptin (10 μg/ml), and the levels of proinflammatory and catabolic factors in synovial fluid and in the cartilage culture media, and SOCS-3 expression in the cartilage were measured. The role of SOCS-3 in leptin signaling was further studied in H4 murine chondrocytes by downregulating SOCS-3 with siRNA.ResultsLeptin-induced expression of matrix metalloproteinases MMP-1, MMP-3, MMP-13, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were higher in the cartilage samples with low SOCS-3 expression. Accordingly, downregulation of SOCS-3 by siRNA in H4 chondrocytes led to enhanced leptin-induced expression of MMP-3, MMP-13, IL-6 and iNOS. Synovial fluid leptin was associated positively, and cartilage SOCS-3 negatively with synovial fluid levels of MMPs in a multivariate model in obese (body mass index (BMI) >30 kg/m2) but not in non-obese (BMI <30 kg/m2) patients.ConclusionsOur results show, for the first time, that SOCS-3 regulates leptin-induced responses in cartilage, and could thus be a future drug target in the treatment or prevention of OA, especially in obese patients.

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“…The resolution of these processes at later phases requires the down-modulation of NF-κB activity by the re-expression of IκBα (350) and the induction of counter regulators such as suppressor of cytokine signaling 3 (SOCS3) (433). Failure to downregulate NF-κB results in the inappropriate survival of neutrophils, chronic inflammation, and tissue damage which is associated with neutrophil-mediated inflammatory disorders such as sepsis, rheumatoid arthritis and acute lung injury (349, 434, 435).…”

Section: Neutrophilsmentioning

confidence: 99%

Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis

et al. 2019

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The transcription factor NF-κB is a central mediator of inflammation with multiple links to thrombotic processes. In this review, we focus on the role of NF-κB signaling in cell types within the vasculature and the circulation that are involved in thrombo-inflammatory processes. All these cells express NF-κB, which mediates important functions in cellular interactions, cell survival and differentiation, as well as expression of cytokines, chemokines, and coagulation factors. Even platelets, as anucleated cells, contain NF-κB family members and their corresponding signaling molecules, which are involved in platelet activation, as well as secondary feedback circuits. The response of endothelial cells to inflammation and NF-κB activation is characterized by the induction of adhesion molecules promoting binding and transmigration of leukocytes, while simultaneously increasing their thrombogenic potential. Paracrine signaling from endothelial cells activates NF-κB in vascular smooth muscle cells and causes a phenotypic switch to a “synthetic” state associated with a decrease in contractile proteins. Monocytes react to inflammatory situations with enforced expression of tissue factor and after differentiation to macrophages with altered polarization. Neutrophils respond with an extension of their life span—and upon full activation they can expel their DNA thereby forming so-called neutrophil extracellular traps (NETs), which exert antibacterial functions, but also induce a strong coagulatory response. This may cause formation of microthrombi that are important for the immobilization of pathogens, a process designated as immunothrombosis. However, deregulation of the complex cellular links between inflammation and thrombosis by unrestrained NET formation or the loss of the endothelial layer due to mechanical rupture or erosion can result in rapid activation and aggregation of platelets and the manifestation of thrombo-inflammatory diseases. Sepsis is an important example of such a disorder caused by a dysregulated host response to infection finally leading to severe coagulopathies. NF-κB is critically involved in these pathophysiological processes as it induces both inflammatory and thrombotic responses.

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SOCS3 dictates the transition of divergent time-phased events in granulocyte TNF-α signaling

Cited by 14 publications

References 49 publications

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis

Catabolic and proinflammatory effects of leptin in chondrocytes are regulated by suppressor of cytokine signaling-3

Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis

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