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Background: Ethanol (EtOH) is known to alter host immune responses and cytokine production. Acute EtOH exposure can suppress tumor necrosis factor (TNF)-α production, which attenuates pulmonary defense against infection. Previous studies in our laboratory show that acute EtOH inhibited TNF-α production by a posttranscriptional process, namely suppression of TNF-α-converting, enzyme-mediated, ectodomain shedding. However, chronic EtOH has been shown to augment TNF-α production, and this has been associated with EtOH-induced liver injury. To further characterize this paradoxical effect of EtOH on TNF-α production, we developed an in vitro model by using Mono Mac 6 cells, a human monocytic cell line. Methods: Mono Mac 6 cells were treated with EtOH (0-75 mM) for 1 to 7 days. TNF-α production was induced by lipopolysaccharide and phorbol myristate acetate and quantitated by enzyme-linked immunosorbent assay. Generation of reactive oxygen species (ROS) was assayed by using a specific fluorogenic reagent. Results: Acute EtOH initially inhibited lipopolysaccharide/phorbol myristate acetate-induced TNF-α production in Mono Mac 6 cells. However, during chronic EtOH exposure, this inhibition was reversed gradually over time. By day 6 after EtOH treatment, Mono Mac 6 cells demonstrated significant up-regulation of TNF-α production. Moreover, chronic EtOH induced the generation of ROS in these Mono Mac 6 cells. Scavenging ROS by Mn(III)tetrakis(1-methyl-4pyridyl)porphyrin pentachloride and N-acetyl-L-cysteine attenuated chronic EtOH-enhanced TNF-α production. Conclusion: These results suggest that ROS induction is involved in EtOH-enhanced TNF-α production by monocytes. This study also provides insight into the mechanisms of alteration of TNF-α production in different EtOH exposure settings. [ABSTRACT FROM AUTHOR]

Alcohol has long been recognized as an immunosuppressive drug and a risk factor for a spectrum of infectious diseases. Among these infections, bacterial pneumonias are most closely correlated with alcohol abuse. One potential mechanism of ethanol-induced immunosuppression is through its ability to suppress alveolar macrophage production of tumor necrosis factor (TNF-α). This defect can be reversed by priming macrophages with interferon-γ (IFN-γ). We hypothesized that macrophage priming in vivo in a model of acute ethanol intoxication could augment pulmonary host defenses. To test this hypothesis, we used adenoviral-mediated gene transfer of the IFN-γ gene. This strategy resulted in prolonged expression of IFN-γ in vivo. Moreover, in a model of acute ethanol intoxication, this vector significantly enhanced lipopolysaccharide-induced TNF-α responses and lung polymorphonuclear leukocyte recruitment. Furthermore, pulmonary host defenses against Klebsiella pneumoniae were were significantly augmented. These enhanced host defenses were not reversed with pretreatment with a polyclonal anti-TNF-α antibody, suggesting that IFN-γ's effect was through a non-TNF-α-dependent mechanism. These data demonstrate that ethanol-induced suppression of pulmonary host defenses can be reversed with IFN-γ gene therapy. [ABSTRACT FROM AUTHOR]

The 37-kDa immature laminin receptor protein (iLRP) is a speciesconserved, universal immunogenic protein that is expressed in all thus-far examined embryonic and early fetal cells of inbred and outbred rodents. It has also been identified in human concepti. It is altered through normal maturation processes to become a non-immunogenic 67-kDa dimeric mature laminin receptor protein (mLRP) in mid-to late gestation in the mammalian fetus. This antigen ceases to be expressed as an active autoimmunogen in the full-term fetus and in the normal differentiating tissues and organs of the neonate or adult organism, apparently due to dimerization, but it is re-expressed as an immunogenic monomer in tumor cells. In this review, we highlight the known mechanisms of immune responses with particular emphasis on the possible role of the 37-kDa oncofetal antigen/immature laminin receptor (OFA/iLRP) in both pregnancy and cancer.