Inhibition of NF-??B Binding Correlates With Increased Nuclear Glucocorticoid Receptor Levels in Acute Alcohol-Treated Human Monocytes

Mandrekar, Pranoti; Bellerose, Gary; Szabó, Gyöngyi

doi:10.1097/00000374-200212000-00015

Cited by 11 publications

(11 citation statements)

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“…5) and inhibition of its resynthesis (37), which could be attributed to decreased NF-B binding in the promoter of the IB␣ gene. Interestingly, although acute alcohol exposure decreases IKK␣ and IKK␤ activity as well as phosphorylation of IB␣, it appears that there was a delayed disappearance of the complexes of p65 and IB␣ from the cytoplasm, as seen in the immunoprecipitation experiments.…”

Section: Discussionmentioning

confidence: 99%

Acute Alcohol Exposure Exerts Anti-Inflammatory Effects by Inhibiting IκB Kinase Activity and p65 Phosphorylation in Human Monocytes

Mandrekar

Jeliazkova

Catalano

et al. 2007

The Journal of Immunology

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Acute alcohol use is associated with impaired immune responses and decreased proinflammatory cytokine production. Our earlier studies have shown that acute alcohol intake inhibits NF-κB DNA binding in an IκBα-independent manner. We report using human peripheral blood monocytes and Chinese hamster ovary cells transfected with CD14 cells that acute alcohol treatment in vitro exerts NF-κB inhibition by disrupting phosphorylation of p65. Immunoprecipitation of p65 and IκBα revealed that acute alcohol exposure for 1 h decreased NF-κB-IκBα complexes in the cytoplasm. Phosphorylation of p65 at Ser536 is mediated by IκB kinase (IKK)β and is required for NF-κB-dependent cellular responses. We show that acute alcohol treatment decreased LPS-induced IKKα and IKKβ activity resulting in decreased phosphorylation of p65 at Ser536. Furthermore, nuclear expression of IKKα increased after alcohol treatment, which may contribute to inhibition of NF-κB. Decreased phosphorylation of nuclear p65 at Ser276 was likely not due to alcohol-induced inhibition of protein kinase A and mitogen- and stress-activated protein kinase-1 activity. Although decreased IκBα phosphorylation after acute alcohol treatment was attributable to reduced IKKβ activity, degradation of IκBα during alcohol exposure was IKKβ-independent. Alcohol-induced degradation of IκBα in the presence of a 26S proteasome inhibitor suggested proteasome-independent IκBα degradation. Collectively, our studies suggest that acute alcohol exposure modulates IκBα-independent NF-κB activity primarily by affecting phosphorylation of p65. These findings further implicate an important role for IKKβ in the acute effects of alcohol in immune cells.

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Section: Discussionmentioning

confidence: 99%

Acute Alcohol Exposure Exerts Anti-Inflammatory Effects by Inhibiting IκB Kinase Activity and p65 Phosphorylation in Human Monocytes

Mandrekar

Jeliazkova

Catalano

et al. 2007

The Journal of Immunology

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“…Ethanol has been shown to activate NF-B in hepatocytes (64), hepatocellular carcinoma cells (65), Kupffer cells (52), and smooth muscle cells (66). By contrast, ethanol has been reported to decrease NF-B binding activity in acinar cells (67), LPS-treated macrophages or monocytes and TNF-or IL-1␤-treated human peripheral blood monocytes (59,60); LPS-treated human vascular endothelial cells (63), and T lymphocytes (61). In some cell types (e.g., monocytes or macrophages), the effects of ethanol on NF-B activation are dependent on IB␣ degradation, whereas, in other cell types (lymphocytes), the effects of ethanol on NF-B activation are IB␣-independent (61).…”

Section: Discussionmentioning

confidence: 99%

Ethanol Blocks Leukocyte Recruitment and Endothelial Cell Activation In Vivo and In Vitro

Saeed

Varma²,

Peng³

et al. 2004

The Journal of Immunology

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Immune system impairment and increased susceptibility to infection among alcohol abusers is a significant but not well-understood problem. We hypothesized that acute ethanol administration would inhibit leukocyte recruitment and endothelial cell activation during inflammation and infection. Using LPS and carrageenan air pouch models in mice, we found that physiological concentrations of ethanol (1–5 g/kg) significantly blocked leukocyte recruitment (50–90%). Because endothelial cell activation and immune cell-endothelial cell interactions are critical regulators of leukocyte recruitment, we analyzed the effect of acute ethanol exposure on endothelial cell activation in vivo using the localized Shwartzman reaction model. In this model, ethanol markedly suppressed leukocyte accumulation and endothelial cell adhesion molecule expression in a dose-dependent manner. Finally, we examined the direct effects of ethanol on endothelial cell activation and leukocyte-endothelial cell interactions in vitro. Ethanol, at concentrations within the range found in human blood after acute exposure and below the levels that induce cytotoxicity (0.1–0.5%), did not induce endothelial cell activation, but significantly inhibited TNF-mediated endothelial cell activation, as measured by adhesion molecule (E-selectin, ICAM-1, VCAM-1) expression and chemokine (IL-8, MCP-1, RANTES) production and leukocyte adhesion in vitro. Studies exploring the potential mechanism by which ethanol suppresses endothelial cell activation revealed that ethanol blocked NF-κB nuclear entry in an IκBα-dependent manner. These findings support the hypothesis that acute ethanol overexposure may increase the risk of infection and inhibit the host inflammatory response, in part, by blocking endothelial cell activation and subsequent immune cell-endothelial cell interactions required for efficient immune cell recruitment.

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“…Kodak X-OMAT 2000A Processor (Kodak, Rochester, NY) was used for film development in the darkroom. The films were scanned and densitometry was performed on the images using Multi Gauge Ver.3.2 image software (Fujifilm Corp., Valhalla, NY) (Mandrekar et al, 2002). …”

Section: Methodsmentioning

confidence: 99%

Micro‐RNA‐155 Deficiency Prevents Alcohol‐Induced Serum Endotoxin Increase and Small Bowel Inflammation in Mice

Lippai

Bala

Catalano

et al. 2014

Alcoholism Clin & Exp Res

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Background Chronic alcohol impairs gut barrier function and induces inflammatory cytokines. The effects of acute alcohol binge on the gut are partially understood. Micro-RNA-155 (miR-155), a modulator of cytokine and T-cell immune response in the gut, stabilizes tumor necrosis factor-α (TNFα) mRNA. Here, we investigated the role of the inflammation modulator miR-155 as well as the effects of acute binge and chronic alcohol feeding in the small bowel (SB) in mice. Methods For the acute alcohol binge, wild-type (WT) mice received 5 g/kg 50% alcohol/d or equal amount of water oral gavage for 3 days. WT and miR-155-deficient (miR-155-knockout [KO]) mice received ethanol containing Lieber-DeCarli or isocaloric control diet for 5 weeks. MiR-155, antimicrobial peptide, regenerating islet-derived 3-beta (Reg3b), inflammation markers, Src homology 2-containing inositol phosphatase-1 (SHIP1), TNFα, and nuclear factor-κB (NF-κB) were measured in proximal intestinal tissue. Endotoxin was measured in the serum. Results Acute alcohol binge enhanced, whereas chronic alcohol feeding decreased, Reg3b mRNA and protein levels in the SB. Both acute binge and chronic alcohol feeding increased serum endotoxin levels, intestinal NF-κB activation and TNFα mRNA levels. However, TNFα protein and miR-155 were increased only after chronic alcohol feeding in the SB. Furthermore, miR-155-KO mice were protected from chronic alcohol-induced increase in serum endotoxin, intestinal TNFα, and NF-κB activation. Also, alcohol-fed miR-155-KO mice had no decrease of Reg3b and SHIP1 levels. Conclusions These results demonstrate that both acute binge and chronic ethanol administration result in increased serum-endotoxin levels. Our study identifies a novel role for miR-155 in chronic alcohol-induced intestinal inflammation and barrier dysfunction.

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Inhibition of NF-??B Binding Correlates With Increased Nuclear Glucocorticoid Receptor Levels in Acute Alcohol-Treated Human Monocytes

Abstract: Our results show that acute alcohol exposure inhibits GR in monocytes by differently affecting ligand- and nonligand-induced GR nuclear translocation. These data also suggest that acute alcohol regulates GR activation in monocytes concomitant to inhibition of NF-kappaB activation.

Cited by 11 publications

References 36 publications

Acute Alcohol Exposure Exerts Anti-Inflammatory Effects by Inhibiting IκB Kinase Activity and p65 Phosphorylation in Human Monocytes

Acute Alcohol Exposure Exerts Anti-Inflammatory Effects by Inhibiting IκB Kinase Activity and p65 Phosphorylation in Human Monocytes

Ethanol Blocks Leukocyte Recruitment and Endothelial Cell Activation In Vivo and In Vitro

Micro‐RNA‐155 Deficiency Prevents Alcohol‐Induced Serum Endotoxin Increase and Small Bowel Inflammation in Mice

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