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Background: Tumor necrosis factor-α (TNF-α), a product of monocytes and macrophages, functions as an important proinflammatory cytokine in the host's response to invading pathogens. Methods: Because both alcohol abuse and human immunodeficiency virus infection affect TNF-α production and are known to frequently coexist, this study examined the effects of simian immunodeficiency virus (SIV) infection and in vitro alcohol exposure on the lipopolysaccharide (LPS)-induced TNF-α response in blood obtained from SIV-negative and -positive animals at the asymptomatic and terminal stages of infection. Results: Spontaneous TNF-α production was undetectable or low in all groups examined. LPS-induced TNF-α production was increased in blood obtained at the asymptomatic (746 ± 226 pg/ml) and terminal (1945 ± 1013 pg/ml) stages, compared with that from SIV-negative animals (210 ± 28 pg/ml), whereas TNF-α messenger RNA content did not differ in LPS-stimulated blood obtained from SIV-negative, asymptomatic SIV-positive, or terminal SIV-positive animals. Ethanol treatment suppressed TNF-α protein production in all groups, whereas TNF-α messenger RNA levels remained unchanged in blood obtained from animals not infected with SIV. Conclusions: Blood cellular elements remain responsive to LPS stimulation with respect to TNF production even into the acquired immunodeficiency syndrome stage of SIV disease. However, intoxicating doses of alcohol suppress this response, and this may contribute to the immunocompromised state of the host. [ABSTRACT FROM AUTHOR]

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]

Background : Human immunodeficiency virus (HIV) infection and alcohol abuse frequently coexist in the host and are known to suppress individually the host response to a variety of opportunistic infections. Methods : This study examined the effects of in vitro ethanol exposure on several functions of polymorphonuclear leukocytes (PMNs) that were obtained from uninfected and simian immunodeficiency virus (SIV)-infected rhesus macaques, at the asymptomatic and terminal stages of infection. Results : The PMNs obtained from rhesus macaques at both the asymptomatic and terminal stage of SIV disease had elevated phagocytic activity and increased CD11b expression compared with PMNs from uninfected animals. In vitro 100 mM ethanol suppressed phagocytosis and CD1lb adhesion molecule expression by PMNs, regardless of the stage of SIV infection. Treatment of PMNs with granulocyte colony-stimulating factor (G-CSF) attenuated the inhibitory effect seen with prior ethanol exposure. Conclusions : Thcsc data demonstrate that the functional state of PMNs from uninfected as well as SIV-infected rhesus macaques is impaired by direct exposure to intoxicating concentrations of ethanol and that this effect can be attenuated by G-CSF. If alcohol intoxication similarly suppressed PMN function in vivo. it would further increase susceptibility of these hosts to secondary infections. Furthermore, G-CSF may be useful in overcoming the suppressive effects of ethanol on PMN function in such patients. [ABSTRACT FROM AUTHOR]

Alcohol's suppressive effects on polymorphonuclear leukocyte (PMN) production and function increases host susceptibility to a wide variety of infections and impairs the ability of these effector cells to seek and destroy invading pathogens. Granulocyte colony-stimulating factor (G-CSF), an important regulator of PMN production and function, is known to be increased in the plasma during infectious episodes. In previous studies we found acute alcohol intoxication to suppress the tumor necrosis factor-α (TNFα) response to in vivo challenges with bacteria or lipopolysaccharide. The present study was initiated to determine the impact of alcohol intoxication on the plasma G-CSF response to Gram-negative infection. For this purpose, rats received an intravenous challenge of Escherichia coli (106 CFU) 30 min after an intraperitoneal injection of ethanol (5.5 g/kg) or an equivalent volume of saline (control). Ethanol-intoxicated rats had a greater 48 hr mortality to live E. coli injection than did unintoxicated animals (45% vs. 8%). Despite an increased bacterial burden in both the lung and liver at 24 hr after initiating E. coli infection in alcohol-intoxicated animals, PMN tissue recruitment, indexed as myeloperoxidase activity, did not differ between control and alcohol-treated rats. Moreover, alcohol suppressed blood PMN phagocytic capacity to a greater extent in animals given alcohol than controls at 5 and 24 hr after initiating infection. In control animals after intravenous E. coli injection, bioactive G-CSF increased in plasma and peaked near 300 ng/ml at 8 hr. In rats pretreated with alcohol, the plasma G-CSF response was markedly suppressed in response to intravenous E. coli (p 0.05). In a second experiment, neutralization of the E. coli-induced plasma TNFα response by pretreatment with anti-TNFα antibody similarly inhibited the plasma G-CSF response. These results support the postulate that alcohol-induced inhibition of TNFα directly contributes to the adverse effects of alcohol on PMN function by suppressing the normal autocrine amplification pathway responsible for G-CSF production. [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 effects of acute ethanol intoxication on neutrophil [polymorphonuclear leukocyte (PMN)] adhesion molecule expression and certain other functional properties during endotoxemia were studied in rats to elucidate the mechanisms underlying the immunosuppressive effects of ethanol. Acute ethanol intoxication was induced by an intraperitoneal injection of 20% ethanol at a dose of 5.5 g of ethanol/kg. Control animals received an intraperitoneal injection of saline. Thirty minutes after intraperitoneal injection, animals were given a 90-min intravenous infusion of Escherichia coli endotoxin (total dose of 112.5 μg/rat in 2.5 ml of saline) or saline. Certain rats received granulocyte colony-stimulating factor (G-CSF; 50 μg/kg in 5% dextrose, subcutaneous injection twice daily) or vehicle pretreatment for 2 days before intravenous endotoxin infusion. Endotoxemia significantly upregulated CD11b/c and CD18 expression on PMNs when compared with those of saline-infused rats. Acute ethanol intoxication inhibited this endotoxin-induced upregulation of CD11b/c and CD18 expression on PMNs. Ethanol intoxication also suppressed the phagocytic activities of PMNs in saline-infused rats, but this suppression failed to reach statistical significance in endotoxin-infused rats. Hydrogen peroxide generation by PMNs in saline- or endotoxin-infused rats was not affected by ethanol intoxication. Histological examination showed extensive PMN sequestration in the liver after endotoxin infusion, and ethanol intoxication significantly attenuated this hepatic sequestration of PMNs. G-CSF pretreatment enhanced neutrophil phagocytosis, CD11b/c and CD18 expression in endotoxin-infused rats, and prevented the ethanol-induced inhibition of neutrophil CD18 expression and phagocytosis. The impairment of β2-integrin expression on PMNs may be one mechanism underlying ethanol-induced defects of neutrophil delivery into tissue sites of infection. G-CSF may be of benefit to the infected alcoholic host by enhancing leukocyte defense functions. [ABSTRACT FROM AUTHOR]