Acute alcohol activates STAT3, AP-1, and Sp-1 transcription factors via the family of Src kinases to promote IL-10 production in human monocytes

Norkina, Oxana; Dolganiuc, Angela; Shapiro, Taryn; Kodys, Karen; Mandrekar, Pranoti; Szabó, Gyöngyi

doi:10.1189/jlb.0207099

Cited by 61 publications

(77 citation statements)

References 78 publications

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“…However, Src kinase activation downstream of a G protein-coupled receptor such as S1P 1 might be a missing communication link (Rivera and Olivera, 2007), although mechanisms of Src activation in response to G protein-coupled receptor agonists are not fully understood (Gutkind, 2000). Src kinase activation is upstream of STAT signaling in human monocytes (Norkina et al, 2007), and one could speculate that Src kinase links S1P receptor activation to STAT activation in our system. Strikingly, in rat aortic vascular smooth muscle cells, S1P-stimulated transactivation of STAT-coupled epidermal growth factor receptor and platelet-derived growth factor ␤ receptor were Src-dependent (Tanimoto et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Weis

Weigert

Knethen

et al. 2009

MBoC

151

128

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Apoptotic cells (AC) are rapidly engulfed by professional phagocytes such as macrophages to avoid secondary necrosis and thus inflammation. Recognition of AC polarizes macrophages toward an anti-inflammatory phenotype, which shows homology to an alternatively activated M2 macrophage. However, mechanistic details provoking these phenotype alterations are incompletely understood. Here, we demonstrate a biphasic up-regulation of heme oxygenase-1 (HO-1), a protein that bears an antiapoptotic as well as an anti-inflammatory potential, in primary human macrophages, which were exposed to the supernatant of AC. Although the first phase of HO-1 induction at 6 h was accomplished by AC-derived sphingosine-1-phosphate (S1P) acting via S1P receptor 1, the second wave of HO-1 induction at 24 h was attributed to autocrine signaling of vascular endothelial growth factor A (VEGFA), whose expression and release were facilitated by S1P. Whereas VEGFA release from macrophages was signal transducer and activator of transcription (STAT) 1-dependent, vascular endothelial growth factor itself triggered STAT1/STAT3 heterodimer formation, which bound to and activated the HO-1 promoter. Knockdown of HO-1 proved its relevance in facilitating enhanced expression of the antiapoptotic proteins Bcl-2 and Bcl-X L , as well as the anti-inflammatory adenosine receptor A 2A . These findings suggest that HO-1, which is induced by AC-derived S1P, is critically involved in macrophage polarization toward an M2 phenotype.

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Weis

Weigert

Knethen

et al. 2009

MBoC

151

128

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“…Ethanol has been reported to inhibit the functioning of multiple components of the immune system; both innate immune cells, such as neutrophils, monocytes, macrophages, and dendritic cells (DCs), and B and effector T cells involved in adaptive immunity are adversely affected in both in vitro and in vivo ethanol exposure models. Several signaling pathways found in innate immune cells, involving cytokines, Toll-like receptors (TLRs) 2, 3, 4, and 9, and their downstream targets, such as NF-B as well as signal transducers and activators of transcription (STAT), have been reported to be affected negatively by acute and chronic ethanol exposure (11,12,(22)(23)(24)27). In addition, secretion of the proinflammatory cytokines interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), and IL-6 has been found to be altered as well (1).…”

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confidence: 99%

Ethanol Inhibits Antigen Presentation by Dendritic Cells

Eken

Ortiz

Wands

2011

Clin. Vaccine Immunol.

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Previous studies suggest that altered virus-specific T-cell responses observed during chronic ethanol exposure may be due to abnormal functioning of dendritic cells (DCs). Here we explored the effects of ethanol on exogenous antigen presentation by DCs. BALB/c, C57BL/6, and CBA/caj mice were fed ethanol or an isocaloric control diet for 8 weeks. The splenic DC population was expanded using an Flt3L expression plasmid via tail vein injection. DCs were purified and assessed for antigen presentation and processing and for peptide-major histocompatibility complex class I and II (MHCI and MHCII) formation on the cell surface. Interleukin-2 (IL-2) was measured as an indicator of antigen-specific T-cell activation by DCs in coculture. Antigen processing and peptide-MHCII complexes were evaluated by flow cytometry. We observed that ethanol not only suppressed allogeneic peptide presentation to T cells by DCs but also altered presentation of exogenous ovalbumin (OVA) peptide 323-339 to an OVA-specific DO11 T-cell line as well as to OVA-sensitized primary T cells. Smaller amounts of peptide-MHCII complexes were found on the DCs isolated from the spleens of ethanol-fed mice. In contrast to MHCII presentation, cross-presentation of exogenous OVA peptide via MHCI by DCs remained intact. More importantly, ethanol-exposed DCs had reduced B7-DC and enhanced ICOS-L (inhibitory) costimulatory molecule expression. Ethanol inhibits exogenous and allogeneic antigen presentation and affects the formation of peptide-MHCII complexes, as well as altering costimulatory molecule expression on the cell surface. Therefore, DC presentation of peptides in a favorable costimulatory protein environment is required to subsequently activate T cells and appears to be a critical target for the immunosuppressive effects of ethanol.

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“…In contrast, although the combined stimulation of 25 mM ethylic alcohol and LPS did not significantly changed IL-10 production after 10 h stimulation, 100mM alcohol and LPS significantly decreased monocyte IL-10 production than LPS alone [36]. Several other studies using a completely different protocol including drinking of alcohol in healthy volunteers and blood receipt after 18-24 hours, which was stimulated with or without LPS, found a significant increase in IL-10 production [37][38][39][40]. These findings do not contrast our results since a shorter timeframe was applied in our experiments in addition to the use of whole blood in an ex-vivo environment.…”

Section: Discussionmentioning

confidence: 85%

“…Acute alcohol exposure in vivo and in vitro induced IL-10 production in human monocytes, with or without LPS stimulation [32,[36][37][38][39][40]41], and thus may interfere with the cell-mediated and humoral immunity by both reducing inflammatory cytokine production and preventing T-cell proliferation [17,36,42].…”

Section: Discussionmentioning

confidence: 99%

Alcohol Effects on TNF-ÃÂ± and IL-10 Production in an Ex-Vivo Model of Whole Blood Stimulated by LPS

Àlex¹,

Gavala²,

Myrianthefs³

et al. 2015

J Psychiatry

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Journal of Psychiatry AbstractAlcohol exposure is related to increased susceptibility to infections. We investigated the effect of acute exposure to alcohol on pro-and anti-inflammatory cytokine production in an ex-vivo model of whole blood stimulation with lipopolysacharide (LPS). Ten ml of whole blood were taken from 24 healthy volunteers (all men) aged 36.5 ± 1.4 years. Each sample was transferred into two tubes, without and with EDTA as anticoagulant, under sterile conditions. We had 14 groups: the control group in which whole blood was incubated without any other intervention, the LPS group in which whole blood was stimulated with LPS alone, and 12 alcohol groups with (6 groups) and without LPS stimulation (6 groups) using six different doses of alcohol (5‚ 12.5‚ 25‚ 50‚ 100 and 200mM). LPS (500pg) was added after pretreatment with alcohol for 10 minutes. Blood samples were diluted 1:10 in RPMI 1640 culture medium (100μl whole blood added in 900μl RPMI 1640), and then alcohol solution and LPS were added according to the study protocol for incubation period of 4 hours at 37°C. Cell culture supernatants were isolated with centrifugation at 1,800rpm, for 5 min at room temperature and stored at -70°C until measurements. Cytokine levels were determined in culture supernatant with the ELISA method. Alcohol had no effect on cytokine production when incubated with whole blood alone. TNF-α IL-6 and IL-10 significantly increased after LPS stimulation. Alcohol had no effect on IL-6 production after LPS challenge but significantly decreased TNF-α and IL-10 production in the presence of LPS challenge at 25mM to 200mM in a dose dependent manner. Conclusively TNF-α and IL-10 were significantly decreased after alcohol exposure in a dose depended manner in a model of whole blood stimulation with LPS exvivo expressing both suppression of pro-and anti-inflammatory response.Keywords: Alcohol; Cytokines; Lipopolysacharide; TNF-α; IL-6; IL-10 Abbreviations: LPS = lipopolysaccharide; TNF-α = Tumor necrosis factor-alpha; IL-6 = Interleukin-6; IL-10 = Interleukin-10

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Acute alcohol activates STAT3, AP-1, and Sp-1 transcription factors via the family of Src kinases to promote IL-10 production in human monocytes

Cited by 61 publications

References 78 publications

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Ethanol Inhibits Antigen Presentation by Dendritic Cells

Alcohol Effects on TNF-ÃÂ± and IL-10 Production in an Ex-Vivo Model of Whole Blood Stimulated by LPS

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Acute alcohol activates STAT3, AP-1, and Sp-1 transcription factors via the family of Src kinases to promote IL-10 production in human monocytes

Cited by 61 publications

References 78 publications

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Ethanol Inhibits Antigen Presentation by Dendritic Cells

Alcohol Effects on TNF-ÃÂ± and IL-10 Production in an Ex-Vivo Model of Whole Blood Stimulated by LPS

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Alcohol Effects on TNF-ÃÂ± and IL-10 Production in an Ex-Vivo Model of Whole Blood Stimulated by LPS