Acute Alcohol Intoxication Suppresses the CXC Chemokine Response During Endotoxemia

Abstract

CXC chemokines play an important role in host defense against infections. Alcohol is a frequently abused drug that inhibits numerous immune functions of the host. This study investigated the effects of alcohol on CXC chemokine macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) responses in rats challenged with intravenous lipopolysaccharide (LPS). Acute ethanol intoxication was induced by an intraperitoneal injection of 20% alcohol (5.5 g/kg). Thirty minutes thereafter, LPS (500 microg/kg) was administered intravenously. In another set of experiments, rats were intravenously administered an anti-tumor necrosis factor-alpha (TNFalpha) neutralizing antibody (10 mg per rat) 2 hr before the LPS challenge. At 1 and 2 hr after the LPS challenge, MIP-2, CINC, and TNFalpha concentrations in the plasma were significantly increased. Alcohol intoxication suppressed the MIP-2, CINC, and TNFalpha responses in the bloodstream during endotoxemia. Alcohol also suppressed the increase in plasma chemotactic activity and polymorphonuclear leukocyte adhesion molecule expression in rats with endotoxemia. MIP-2 and CINC messenger RNA (mRNA) expression was significantly increased 1 hr after endotoxemia in the lung, liver, and spleen. Alcohol suppressed the up-regulation of MIP-2 mRNA expression in all of these organs and CINC mRNA expression in the lungs of rats with endotoxemia. TNFalpha neutralization minimally inhibited plasma CINC and MIP-2 responses during endotoxemia and did not suppress the increase in plasma chemotactic activity. These results show that alcohol suppresses the systemic CXC chemokine response to LPS, which is not primarily mediated by ethanol-induced suppression of TNFalpha. This disruption of host-defense function may serve as one mechanism underlying the increased risk of infectious diseases in hosts who abuse alcohol.