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The Opposite Effects of Acute and Chronic Alcohol on Lipopolysaccharide-Induced Inflammation Are Linked to IRAK-M in Human Monocytes¹

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

Impaired host defense after alcohol use is linked to altered cytokine production, however, acute and chronic alcohol differently modulate monocyte/macrophage activation. We hypothesized that in human monocytes, acute alcohol induces hyporesponsiveness to LPS, resulting in decreased TNF-, whereas chronic alcohol increases TNF- by sensitization to LPS. We found that acute alcohol increased IL-1R-associated kinase-monocyte (IRAK-M), a negative regulator of IRAK-1, in human monocytes. This was associated with decreased IB kinase activity, NFB DNA binding, and NFB-driven reporter activity after LPS stimulation. In contrast, chronic alcohol decreased IRAK-M expression but increased IRAK-1 and IKK kinase activities, NFB DNA binding, and NFB-reporter activity. Inhibition of IRAK-M in acute alcohol-exposed monocytes using small interfering RNA restored the LPS-induced TNF- production whereas over-expression of IRAK-M in chronic alcohol macrophages prevented the increase in TNF- production. Addition of inhibitors of alcohol metabolism did not alter LPS signaling and TNF- production during chronic alcohol exposure. IRAK-1 activation induces MAPKs that play an important role in TNF- induction. We determined that acute alcohol decreased but chronic alcohol increased activation of ERK in monocytes and ERK inhibitor, PD98059, prevented the chronic alcohol-induced increase in TNF-. In summary, inhibition of LPS-induced NFB and ERK activation by acute alcohol leads to hyporesponsiveness of monocytes to LPS due to increased IRAK-M. In contrast, chronic alcohol sensitizes monocytes to LPS through decreased IRAK-M expression and activation of NFB and ERK kinases. Our data indicate that IRAK-M is a central player in the opposite regulation of LPS signaling by different lengths of alcohol exposure in monocytes.

²Address correspondence and reprint requests to Drs. Gyongyi Szabo and Pranoti Mandrekar, University of Massachusetts Medical School, Department of Medicine, 364 Plantation Street, Worcester, MA 01605. E-mail addresses: gyongyi.szabo{at}umassmed.edu and pranoti.mandrekar{at}umassmed.edu

¹ This work was supported by Public Health Service Grant No. AA011576 (to G.S.) and AA008577 (to G.S.) from the National Institute of Alcohol Abuse and Alcoholism and by the resources of University of Massachusetts Medical School Center for AIDS Research (Grant 5P30 AI42845) and the Diabetes Endocrinology Research Center (PHS Grant DK32520) 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.