Flavanoids induce expression of the suppressor of cytokine signalling 3 (<i>SOCS3</i>) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells

Wiejak, Jolanta; Dunlop, Julia; Mackay, Simon P.; Yarwood, Stephen J.

doi:10.1042/bj20130481

Cited by 52 publications

(47 citation statements)

References 48 publications

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“…However, AMPK is commonly linked with the NF-κB pathway to explain inflammation control27. Previously, naringenin was found to directly activate AMPK in vascular endothelial cells and muscle cells2829. Therefore, we speculated that naringenin may induce ATF3 upregulation by activating AMPK.…”

Section: Discussionmentioning

confidence: 95%

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

Liu

Wang

Fan

et al. 2016

Sci Rep

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Excessive activation of the TLR4 signalling pathway is critical for inflammation-associated disorders, while negative regulators play key roles in restraining TLR4 from over-activation. Naringenin is a citrus flavonoid with remarkable anti-inflammatory activity, but the mechanisms underlying its inhibition of LPS/TLR4 signalling are less clear. This study investigated the molecular targets and therapeutic effects of naringenin in vitro and in vivo. In LPS-stimulated murine macrophages, naringenin suppressed the expression of TNF-α, IL-6, TLR4, inducible NO synthase (iNOS), cyclo-oxygenase-2 (COX2) and NADPH oxidase-2 (NOX2). Naringenin also inhibited NF-κB and mitogen-activated protein kinase (MAPK) activation. However, it did not affect the IRF3 signalling pathway or interferon production, which upregulate activating transcription factor 3 (ATF3), an inducible negative regulator of TLR4 signalling. Naringenin was demonstrated to directly increase ATF3 expression. Inhibition of AMPK and its upstream calcium-dependent signalling reduced ATF3 expression and dampened the anti-inflammatory activity of naringenin. In murine endotoxaemia models, naringenin ameliorated pro-inflammatory reactions and improved survival. Furthermore, it induced AMPK activation in lung tissues, which was required for ATF3 upregulation and the enhanced anti-inflammatory activity. Overall, this study reveals a novel mechanism of naringenin through AMPK-ATF3-dependent negative regulation of the LPS/TLR4 signalling pathway, which thereby confers protection against murine endotoxaemia.

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Section: Discussionmentioning

confidence: 95%

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

Liu

Wang

Fan

et al. 2016

Sci Rep

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“…Whereas other studies have showed different results regarding the effect of STAT activation on chemokine and cytokine secretion. In human umbilical vein endothelial cells, MCP-1 mRNA expression was dependent on STAT3 activation (Wiejak et al, 2013). According to our results, we suggest that STAT1 activation by IFN-β plays a key role in the pro-inflammatory response of cultured CF.…”

Section: Discussionmentioning

confidence: 99%

IFN-β Plays Both Pro- and Anti-inflammatory Roles in the Rat Cardiac Fibroblast Through Differential STAT Protein Activation

et al. 2018

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Cardiac fibroblasts (CFs) contribute to theinflammatory response to tissue damage, secreting both pro- and anti-inflammatory cytokines and chemokines. Interferon beta (IFN-β) induces the phosphorylation of signal transducer and activator of transcription (STAT) proteins through the activation of its own receptor, modulating the secretion of cytokines and chemokines which regulate inflammation. However, the role of IFN-β and STAT proteins in modulating the inflammatory response of CF remains unknown. CF were isolated from adult male rats and subsequently stimulated with IFN-β to evaluate the participation of STAT proteins in secreting chemokines, cytokines, cell adhesion proteins expression and in their capacity to recruit neutrophils. In addition, in CF in which the TRL4 receptor was pre-activated, the effect of INF-β on the aforementioned responses was also evaluated. Cardiac fibroblasts stimulation with IFN-β showed an increase in STAT1, STAT2, and STAT3 phosphorylation. IFN-β stimulation through STAT1 activation increased proinflammatory chemokines MCP-1 and IP-10 secretion, whereas IFN-β induced activation of STAT3 increased cytokine secretion of anti-inflammatory IL-10. Moreover, in TLR4-activated CF, IFN-β through STAT2 and/or STAT3, produced an anti-inflammatory effect, reducing pro-IL-1β, TNF-α, IL-6, MCP-1, and IP-10 secretion; and decreasing neutrophil recruitment by decreasing ICAM-1 and VCAM-1 expression. Altogether, our results indicate that IFN-β exerts both pro-inflammatory and anti-inflammatory effects in non-stimulated CF, through differential activation of STAT proteins. When CF were previously treated with an inflammatory agent such as TLR-4 activation, IFN-β effects were predominantly anti-inflammatory.

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“…An additional time point of 6 h was performed for IL-10 treatments. For experiments assessing SOCS3 stabilization, THP-1 cells were pre-incubated with or without IL-10 (20 ng/ml) for 30 min before the addition of IL-6 (10 ng/ml) in the presence or absence of 10 μM of the proteasome inhibitor MG132 (Calbiochem, Merck Millipore) for 5 h. To verify the effects of MG132 in preventing the proteolytic degradation of newly synthesized SOCS3 by the ubiquitin–proteasome system (16) aditional experiments were performed in THP-1 cells pre-incubated in the absence or presence of MG132 (10 μM) for 30 min before the addition of IL-6 (10 ng/ml) for 5 h. In some experiments, LPS stimulation was performed in the presence of a mouse monoclonal anti-human IL-10 receptor (10 μg/ml) or control non-immune mouse immunoglobin (IgG) (R&D Systems). At the end of the incubation periods, cells and supernatants were collected for futher analysis.…”

Section: Methodsmentioning

confidence: 99%

Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue

Titos¹,

Rius²,

López‐Vicario³

et al. 2016

The Journal of Immunology

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Persistent activation of the innate immune system greatly influences the risk of developing metabolic complications associated with obesity. In this study, we explored the therapeutic potential of the specialized pro-resolving mediator (SPM) resolvin D1 (RvD1) to actively promote the resolution of inflammation in human visceral adipose tissue from obese patients. By means of LC-MS/MS-based metabololipidomic analysis we identified unbalanced production of SPMs (i.e. D- and E-series resolvins, protectin D1, maresin 1 and lipoxins) with respect to inflammatory lipid mediators (i.e. leukotriene B4 and prostaglandins) in omental adipose tissue from obese patients. In parallel, high-throughput transcriptomic analysis revealed a unique signature in this tissue characterized by an overactivation of the interleukin (IL)-10 signaling pathway. Incubation of inflamed obese visceral adipose tissues and human macrophages with RvD1 limited the excessive activation of the IL-10 pathway by reducing phosphorylation of signal transducer and activator of transcription (STAT) proteins. Of interest, RvD1 blocked STAT-1 and its target inflammatory genes (i.e. CXCL9) as well as persistent STAT3 activation without affecting the IL-10 anti-inflammatory response characterized by inhibition of IL-6, IL-1β, IL-8 and TNFα. Furthermore, RvD1 promoted resolution by enhancing the expression of the IL-10-target gene heme oxygenase-1 by mechanisms depending on p38 mitogen-activated protein kinase (MAPK) activity. Together, our data show that RvD1 can tailor the quantitative and qualitative responses of human inflamed adipose tissue to IL-10 and provide a mechanistic basis for the immunoresolving actions of RvD1 in this tissue. These findings may have potential therapeutic implications in obesity-related insulin resistance and other metabolic complications.

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Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL-6-activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells

Cited by 52 publications

References 48 publications

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

IFN-β Plays Both Pro- and Anti-inflammatory Roles in the Rat Cardiac Fibroblast Through Differential STAT Protein Activation

Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue

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