Acute alcohol intoxication suppresses the pulmonary ELR-negative CXC chemokine response to lipopolysaccharide.
Alcohol abuse impairs the pulmonary immune response to infection and increases the morbidity and mortality of bacterial pneumonia. Acute alcohol intoxication suppresses lung expression of CXC chemokines bearing the Glu-Leu-Arg motif (ELR+) following lipopolysaccharide (LPS) challenge, but its effect on the structurally related ELR- CXC chemokines, which attract T cells, is unknown. We therefore investigated the effect of acute alcohol intoxication on the pulmonary response to intratracheal (i.t.) LPS challenge for the ELR- CXC chemokines monokine induced by gamma (MIG or CXCL9), interferon-inducible protein 10 (IP-10 or CXCL10), and interferon-inducible T cell alpha chemoattractant (I-TAC or CXCL11). Male C57BL/6 or C3H/HeN mice were given an intraperitoneal injection of ethanol (3.0 g/kg) or phosphate buffered saline 30 min before i.t. LPS challenge. Chemokine mRNA transcripts were measured at 0, 2, 6, and 16 h. Acute alcohol intoxication inhibited the lung's expression of all three chemokine genes in response to LPS. Lung IFN-gamma mRNA was also inhibited by acute intoxication over the same time course. The in vitro effect of ethanol on chemokine secretion was further studied in the MH-S alveolar macrophage cell line. IP-10, MIG, and I-TAC in response to LPS were enhanced by exogenous interferon (IFN)-gamma, and these responses were blunted by exposure to ethanol. Alcohol exposure did not affect MH-S cell nuclear factor kappa beta p65 nuclear localization during challenge, despite dose-dependent inhibition of Erk 1/2 phosphorylation. In addition, phospho-signal transduction and activator of transcription 1 was not decreased in the presence of acute ethanol, thereby indicating that acute intoxication does not affect IFN-gamma signaling in MH-S cells. Recruitment of CD3+ T cells into the alveolar space 4 days after LPS challenge was moderately impaired by acute ethanol intoxication. These results implicate acute ethanol intoxication as a significant inhibitor of lymphocyte chemoattractant expression during pulmonary inflammation.
Happel
Kyle I
KI
Louisiana State University Health Sciences Center, Alcohol Research Center, Section of Pulmonary/Critical Care, 1901 Perdido Street, Suite 3205, New Orleans, LA 70112, USA. Khappe@lsuhsc.edu
Rudner
Xiaowen
X
Quinton
Lee J
LJ
Movassaghi
Jennifer L
JL
Clark
Charles
C
Odden
Anthony R
AR
Zhang
Ping
P
Bagby
Gregory J
GJ
Nelson
Steve
S
Shellito
Judd E
JE
D000435:Alcoholic Intoxication / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000633:toxicity*; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004927:Escherichia coli Infections / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D002492:Central Nervous System Depressants; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D000431:Ethanol; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases