Papers by JUAN CAMILO MENDEZ RENDON
Alcohol, 2009
Impaired host defense is linked to alcohol abuse due to alterations in inflammatory mediator prod... more Impaired host defense is linked to alcohol abuse due to alterations in inflammatory mediator production. We hypothesized that in human monocytes, acute alcohol induces hyporesponsiveness to LPS leading to decreased production of the proinflammatory cytokine, TNFa whereas chronic alcohol increases TNFa by sensitization to LPS. Human adherence-isolated blood monocytes were exposed to 25 mM alcohol for 7 days (chronic) and then treated with LPS (100ng/ml) for 18 hrs. For acute or short-term treatment, cells were exposed to LPS and 25 mM alcohol for 18 hrs. TNFa levels were analyzed by ELISA and IRAK-M mRNA and protein determined by real-time PCR and western blotting respectively. Our results show that acute alcohol decreases LPS-induced TNFa production (p ! 0.001) compared to LPS treatment alone. Concomitantly, LPS-induced IRAK-M, a negative regulator of inflammation, is increased after acute alcohol exposure. In contrast, chronic alcohol increases LPS-induced TNFa (p ! 0.001) with simultaneously decreased IRAK-M expression in these cells. Signaling molecules downstream to TLR4/ IRAK-M were also investigated to determine their regulation by acute and chronic alcohol exposure in monocytes. Acute alcohol decreases IRAK-1 and IKK activity, NFkB DNA binding and NFkB-driven reporter activity after LPS stimulation but chronic alcohol increases IRAK-1 and IKK kinase activities, NFkB DNA binding and NFkB-reporter activity. Inhibition of IRAK-M in acute-alcohol exposed monocytes using siRNA restores the LPS-induced TNFa whereas over-expression of IRAK-M in chronic alcohol macrophages prevents the increase in TNFa production. Addition of inhibitors of alcohol metabolism did not alter LPS signaling and TNFa production during chronic alcohol exposure. In summary, increased IRAK-M by acute alcohol leads to hyporesponsiveness of monocytes to LPS and reduced TNFa. In contrast, chronic alcohol sensitizes monocytes to LPS through decreased IRAK-M expression and results in increased TNFa production. Our data indicate that IRAK-M plays a central role in the differential regulation of LPS signaling by different lengths of alcohol exposure in monocytes.
Zona Proxima No 18, Apr 4, 2013
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Papers by JUAN CAMILO MENDEZ RENDON