Acute Alcohol Inhibits the Induction of Nuclear Regulatory Factor ??B Activation Through CD14/Toll-Like Receptor 4, Interleukin-1, and Tumor Necrosis Factor Receptors: A Common Mechanism Independent of Inhibitory ??B?? Degradation?

Mandrekar, Pranoti; Dolganiuc, Angela; Bellerose, Gary; Kodys, Karen; Romics, L; Nizamani, Rabia; Szabó, Gyöngyi

doi:10.1097/00000374-200211000-00002

Cited by 22 publications

(36 citation statements)

References 38 publications

(22 reference statements)

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“…Previous data suggested that universal inhibition of NF-B binding by alcohol via various receptor systems occurs independent of IB␣ degradation (24). In this study, we investigated the effects of acute alcohol exposure on IB␣-independent mechanisms of NF-B activation.…”

Section: Acute Alcohol Consumption Inhibits Lps-induced Nf-b Binding mentioning

confidence: 97%

“…1A). CHO cells expressing endogenous TLR4 and stably transfected with human CD14 provide an ideal system for investigation of TLR4-CD14-mediated NF-B activation (24). Alcohol was used at a physiologically relevant 25 mM dose that corresponds to blood alcohol levels (0.1 g/dl) slightly above the legal limit.…”

Section: Acute Alcohol Consumption Inhibits Lps-induced Nf-b Binding mentioning

confidence: 99%

“…However, in the presence of a bacterial stimulus, such as LPS, acute ethanol exposure decreased NF-B DNA binding of the p65-p50 heterodimer complex, which is responsible for transactivation of target genes (23). Previous studies have also shown that acute alcohol treatment affects NF-B nuclear translocation and DNA binding in human monocytes without affecting LPS-induced IB␣ degradation, regardless of the stimuli, through various inflammatory receptors (24). Hence, it was postulated that acute alcohol exposure could inhibit NF-B in an IB␣-independent manner.…”

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confidence: 96%

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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: Acute Alcohol Consumption Inhibits Lps-induced Nf-b Binding mentioning

confidence: 97%

Section: Acute Alcohol Consumption Inhibits Lps-induced Nf-b Binding mentioning

confidence: 99%

mentioning

confidence: 96%

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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 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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“…139 In contrast to chronic alcohol consumption, acute alcohol exposure inhibits TLR4 signaling in monocytes and macrophages after in vitro as well as in vivo alcohol treatment in mice leading to decreased LPS-induced TNF␣ production. [140][141][142] Acute alcohol administration also suppressed TLR3 downstream signaling. 143 Various laboratories have shown distinct roles for TLR-associated molecules such as CD14, TLR4 and LBP in ALD as well as for oxidative stress-related molecules such as NADPH oxydase (p47 phox) and iNOS.…”

Section: Prrs In Liver Diseasesmentioning

confidence: 91%