Acute alcohol intoxication suppresses the CXC chemokine response during endotoxemia.
BACKGROUND
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Zhang
Ping
P
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Alcohol Research Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Bagby
Gregory J
GJ
Boé
Darren M
DM
Zhong
Qiu
Q
Schwarzenberger
Paul
P
Kolls
Jay K
JK
Summer
Warren R
WR
Nelson
Steve
S
D000435:Alcoholic Intoxication / Q000276:immunology*; D000818:Animals; D000918:Antibody Specificity; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000097:blood; D019446:Endotoxemia / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D006133:Growth Substances / Q000096:biosynthesis / Q000097:blood; D007166:Immunosuppressive Agents / Q000097:blood* / Q000633:toxicity; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C513297:Cxcl1 protein, rat; C404915:Cxcl2 protein, mouse; C513296:Cxcl2 protein, rat; D000939:Epitopes; D006133:Growth Substances; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha