Release of anti-HIV mediators after administration of leukotriene B4 to humans.
BACKGROUND
CD8(+) T cells can control human immunodeficiency virus (HIV) through the lysis of infected cells and the release of soluble mediators, such as macrophage inflammatory protein (MIP)-1 beta, which prevent entry of HIV and/or inhibit HIV replication. Because neutrophils represent a major source of alpha-defensins and, to a lesser extent, MIP-1 beta, we determined whether leukotriene B(4) (LTB(4)), a potent neutrophil agonist, would trigger the release of these 2 anti-HIV peptides.


METHODS
Plasma samples from HIV-uninfected subjects receiving intravenous bolus of LTB(4) were analyzed for alpha-defensins and MIP-1 beta levels by use of enzyme-linked immunosorbent assay. Furthermore, in vitro analysis of intracellular and secreted levels of alpha-defensins of resting and LTB(4)-activated neutrophils from HIV-uninfected and HIV-infected subjects were determined. LTB(4) modulation of CD63 and CD66b markers associated with degranulation were studied by use of flow cytometry. Chemotaxis of neutrophils from HIV-uninfected and HIV-infected subjects toward LTB(4) or interleukin (IL)-8 was determined by use of migration assays.


RESULTS
Administration of LTB(4) to humans caused a dose-dependent plasmatic increase in alpha-defensins and MIP-1 beta proteins, with peak levels observed 2 h after administration of LTB(4). Neutrophils isolated from HIV-infected and HIV-uninfected subjects contained similar levels of stored alpha-defensins that were effectively secreted in vitro, in response to LTB(4) activation. Chemotaxis of neutrophils toward LTB(4) or IL-8 was identical among the groups of subjects.


CONCLUSIONS
LTB(4) induced the secretion alpha-defensins and MIP-1 beta. Neutrophils from HIV-infected subjects were fully responsive to LTB(4), which highlights a potential usefulness of this lipid mediator in the management of HIV infection.
Flamand
Louis
L
Department of Anatomy and Physiology, Laval University, and Rheumatology and Immunology Research Center, CHUL Research Center, Sainte-Foy, Quebec, Canada.
Borgeat
Pierre
P
Lalonde
Richard
R
Gosselin
Jean
J
D015703:Antigens, CD / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology; D054407:Chemokine CCL4; D002633:Chemotaxis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000494:pharmacology; D007975:Leukotriene B4 / Q000276:immunology / Q000494:pharmacology*; D019402:Macrophage Inflammatory Proteins / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000276:immunology; D060149:Tetraspanin 30; D023084:alpha-Defensins / Q000097:blood* / Q000276:immunology / Q000378:metabolism
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C554586:CD63 protein, human; C504120:CEACAM8 protein, human; D015815:Cell Adhesion Molecules; D054407:Chemokine CCL4; D058851:GPI-Linked Proteins; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D010980:Platelet Membrane Glycoproteins; D060149:Tetraspanin 30; D023084:alpha-Defensins; D007975:Leukotriene B4