title: Alcohol impairs the myeloid proliferative response to bacteremia in mice by inhibiting the stem cell antigen-1/ERK pathway.
abstract: Enhancement of stem cell Ag-1 (Sca-1) expression by myeloid precursors promotes the granulopoietic response to bacterial infection. However, the underlying mechanisms remain unclear. ERK pathway activation strongly enhances proliferation of hematopoietic progenitor cells. In this study, we investigated the role of Sca-1 in promoting ERK-dependent myeloid lineage proliferation and the effects of alcohol on this process. Thirty minutes after i.p. injection of alcohol, mice received i.v. challenge with 5 × 10(7) Escherichia coli for 8 or 24 h. A subset of mice received i.v. BrdU injection 20 h after challenge. Bacteremia increased Sca-1 expression, ERK activation, and proliferation of myeloid and granulopoietic precursors. Alcohol administration suppressed this response and impaired granulocyte production. Sca-1 expression positively correlated with ERK activation and cell cycling, but negatively correlated with myeloperoxidase content in granulopoietic precursors. Alcohol intoxication suppressed ERK activation in granulopoietic precursors and proliferation of these cells during bacteremia. Granulopoietic precursors in Sca-1(-/-) mice failed to activate ERK signaling and could not increase granulomacrophagic CFU activity following bacteremia. These data indicate that Sca-1 expression promotes ERK-dependent myeloid cell proliferation during bacteremia. Suppression of this response could represent an underlying mechanism for developing myelosuppression in alcohol-abusing hosts with severe bacterial infection.
authors.affiliation: Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: John Nicholas
authors.initials: JN
authors.lastname: Melvan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Siggins
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Connie
authors.initials: C
authors.lastname: Porretta
authors.forename: Steve
authors.initials: S
authors.lastname: Nelson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bagby
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000435:Alcoholic Intoxication / Q000276:immunology*; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D016470:Bacteremia / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000276:immunology; D000431:Ethanol / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000276:immunology; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism*; D009195:Peroxidase / Q000096:biosynthesis; D015398:Signal Transduction
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D000431:Ethanol; D009195:Peroxidase