Molecular mechanisms of inhibition of ubiquitination by alcohol

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The aim in the present study was to clarify role of NF-kappaB, a ubiquitous protein related to cell survival, in ethanol action. First, I summarized relationship between ethanol and activation of NF-kappaB by previous reports and pharmacokinetics of ethanol. On these bases, we examined the activation mechanisms of NF-kappaB by ethanol. The results summarize as follows.1. Acute ethanol acitivated NF-kappaB and induces inhibitor of apoptosis proteins (IAPs). NF-kappaB activation and IAP expression induced by ethanol were decreased by MG135, a proteasome inhibitor. As NF-kappaB was increased by the proteasome inhibitor, JNK-AP-1 pathway, a cell death signaling, was activated. These findings suggest that ethanol-induced NF-kappaB activation regulates JNK-AP-1 pathway related to cell death by regulation of IAPs.2. Acute ethanol induced activation of JNK and Akt under inhibition of ADH, and activation of JNK was reduced by an antioxidant. Akt binding to JIP1 was active, while JNK binding to JIP1 was inactive.3. Ethanol acted any pathways between IGF receptor and FOXO by using several knockout C.elegans, which reduced life span in C.elegans.4. Ethanol activated NF-kappaB via TLR4- signaling. Co treatment with ethanol and LPS accumulated NF-kappaB activation to induce proinflammatory cytokines, i.e. TNF-alpha, IL-1beta, IL-10 and so on.5.