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Acute Alcohol Exposure Exerts Anti-Inflammatory Effects by Inhibiting IB Kinase Activity and p65 Phosphorylation in Human Monocytes¹

Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605

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-B DNA binding in an IB-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-B inhibition by disrupting phosphorylation of p65. Immunoprecipitation of p65 and IB revealed that acute alcohol exposure for 1 h decreased NF-B-IB complexes in the cytoplasm. Phosphorylation of p65 at Ser⁵³⁶ is mediated by IB kinase (IKK) and is required for NF-B-dependent cellular responses. We show that acute alcohol treatment decreased LPS-induced IKK and IKK activity resulting in decreased phosphorylation of p65 at Ser⁵³⁶. Furthermore, nuclear expression of IKK increased after alcohol treatment, which may contribute to inhibition of NF-B. 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 IB phosphorylation after acute alcohol treatment was attributable to reduced IKK activity, degradation of IB during alcohol exposure was IKK-independent. Alcohol-induced degradation of IB in the presence of a 26S proteasome inhibitor suggested proteasome-independent IB degradation. Collectively, our studies suggest that acute alcohol exposure modulates IB-independent NF-B activity primarily by affecting phosphorylation of p65. These findings further implicate an important role for IKK in the acute effects of alcohol in immune cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant RO1 AA11576 from the Public Health Service, National Institute of Alcohol Abuse and Alcoholism and its contents are solely the responsibility of the authors and do not necessarily represent the views of the National Institute of Alcohol Abuse and Alcoholism.

² Address correspondence and reprint requests to Dr. Gyongyi Szabo, Department of Medicine, Lazare Research Building Room 215, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605. E-mail address: gyongyi.szabo{at}umassmed.edu

³ Abbreviations used in this paper: PKA, protein kinase A; PKAc, PKA catalytic subunit; CHO, Chinese hamster ovary; IKK, IB kinase; TBP, TATA-binding protein; MSK, mitogen- and stress-activated protein kinase; CBP, CREB-binding protein.

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				P. Mandrekar, S. Bala, D. Catalano, K. Kodys, and G. Szabo The Opposite Effects of Acute and Chronic Alcohol on Lipopolysaccharide-Induced Inflammation Are Linked to IRAK-M in Human Monocytes J. Immunol., July 15, 2009; 183(2): 1320 - 1327. [Abstract] [Full Text] [PDF]