The mechanisms underlying alcohol-induced liver disease (ALD) 1 remains incompletely understood. Nevertheless, it is widely recognized that the oxidative metabolism of ethanol elicits a complex interplay of factors, including mitochondrial dysfunction, autoimmune-mediated cell injury, oxidative stress, and overproduction of inflammatory cytokines, which contribute to the development of the disease (1-4).Acetaldehyde, a product of the oxidative metabolism of ethanol, is a very reactive intermediate that has been suggested to have a pathogenic role in ALD (1, 2). Indeed, there is a correlation between acetaldehyde generation within the liver and cell injury. The impairment of the low K m mitochondrial acetaldehyde dehydrogenase in perivenous hepatocytes indicates the existence of an acetaldehyde gradient along the liver acinus being greater in the perivenous zone of the liver, the area where most of the ethanol-induced liver injury is seen in both alcoholic patients and experimental animal models (2, 5-7). Furthermore, previous in vivo and in vitro studies have revealed the ability of acetaldehyde to form covalent adducts with various proteins that are thought to lead to altered liver function and structure (1, 2). In addition to these effects, it has been shown that acetaldehyde increases the transcription of collagen in several cell types (8 -11) mediated by enhanced DNA binding of transcription factors NF-1 and SP-1 to specific sites located in the promoter of the ␣2(I) collagen gene (12, 13).In eukaryotes, regulation of gene expression can be dramatically enhanced by the binding of sequence-specific DNA-binding proteins to promoter cis-acting elements. NF-B and AP-1 are transcription factors whose role in gene regulation is widely recognized (14, 15). The DNA binding subunits of NF-B belong to a multigene family that comprise several members including p50, p65 (Rel A), c-Rel, p-52, and RelB. These proteins share a domain required for DNA binding, forming homo-and heterodimers, IB binding, and nuclear localization (15-17). On the other hand, AP-1 is a transcriptional activator composed of members of the Jun and Fos families. These proteins associate to form homo-and heterodimer complexes through a leucine zipper domain that bind to a common site (18 -21). The final step in the gene regulation of both transcription factors is the translocation of the active complex to the nuclei followed by the binding to specific DNA sequences. However, unlike the AP-1 complex, NF-B activation combines several mechanisms used by other transcription factors such as phosphorylation at specific residues of the inhibitory subunit IB followed by its degradation and translocation of the active NF-B into the nuclei. Both transcription factors become activated by a wide variety of stimuli, including growth factors, cytokines, UV irradiation, and oxidative stress (18,21,22). NF-B and AP-1 control the inducible expression of a variety of genes that are involved in immune response as well as inflammatory and cellular defense mechanisms, i...
While the present findings demonstrate the anti-inflammatory role of IL-4 in preventing the expression of IL-8 by Ac, the regulation of chemokines by anti-inflammatory cytokines is complex and depends on the cellular lineage.
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