The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes
Department of Medicine, Division of Gastroenterology; Department of Medicine, Rheumatology Division
Acute Disease; Alcoholism; Chronic Disease; Ethanol; Extracellular Signal-Regulated MAP Kinases; Humans; Inflammation; Interleukin-1 Receptor-Associated Kinases; Lipopolysaccharides; Macrophages; Monocytes; NF-kappa B; Signal Transduction; Time Factors; Tumor Necrosis Factor-alpha
Gastroenterology | Immunology and Infectious Disease
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-alpha, whereas chronic alcohol increases TNF-alpha 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 IkappaB alpha kinase activity, NFkappaB DNA binding, and NFkappaB-driven reporter activity after LPS stimulation. In contrast, chronic alcohol decreased IRAK-M expression but increased IRAK-1 and IKK kinase activities, NFkappaB DNA binding, and NFkappaB-reporter activity. Inhibition of IRAK-M in acute alcohol-exposed monocytes using small interfering RNA restored the LPS-induced TNF-alpha production whereas over-expression of IRAK-M in chronic alcohol macrophages prevented the increase in TNF-alpha production. Addition of inhibitors of alcohol metabolism did not alter LPS signaling and TNF-alpha production during chronic alcohol exposure. IRAK-1 activation induces MAPKs that play an important role in TNF-alpha 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-alpha. In summary, inhibition of LPS-induced NFkappaB 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 NFkappaB 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.
DOI of Published Version
J Immunol. 2009 Jul 15;183(2):1320-7. Epub 2009 Jun 26. Link to article on publisher's site
Journal of immunology (Baltimore, Md. : 1950)
Mandrekar, Pranoti; Bala, Shashi; Catalano, Donna; Kodys, Karen; and Szabo, Gyongyi, "The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes" (2009). Gastroenterology Publications and Presentations. 66.