title: The opposite effects of acute and chronic alcohol on lipopolysaccharide-induced inflammation are linked to IRAK-M in human monocytes.
abstract: 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.
authors: University of Massachusetts Medical School, Department of Medicine, Worcester, MA 01605, USA. pranoti.mandrekar@umassmed.edu
authors: Pranoti
authors: P
authors: Mandrekar
authors: Shashi
authors: S
authors: Bala
authors: Donna
authors: D
authors: Catalano
authors: Karen
authors: K
authors: Kodys
authors: Gyongyi
authors: G
authors: Szabo
mesh_terms: D000208:Acute Disease; D000437:Alcoholism; D002908:Chronic Disease; D000431:Ethanol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000502:physiology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008264:Macrophages / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases