title: Role of lipids in killing mycobacteria by macrophages: evidence for NF-kappaB-dependent and -independent killing induced by different lipids.
abstract: We have shown that several lipids can modulate the macrophage innate immune response against mycobacteria and enhance their killing. Since NF-kappaB is required for mycobacterial killing, we tested the ability of lipids to activate NF-kappaB in uninfected macrophages and those infected with mycobacteria. In uninfected cells, sphingomyelin (SM), phosphatidylinositol-4-phosphate (PIP) and arachidonic acid (AA) enhanced NF-kappaB activation and the cell surface expression of CD69, a macrophage activation marker regulated by NF-kappaB. Sphingosine (Sph), sphingosine-1-phosphate (S1P), diacylglycerol (DAG), eicosapentanoic acid (EPA) and phosphatidyl choline (PC) failed to activate either NF-kappaB or CD69. Ceramide (Cer) activated CD69 expression without activating NF-kappaB. In Mycobacterium smegmatis-infected cells, NF-kappaB was transiently activated in a manner that was enhanced by SM, PIP and AA. In contrast Mycobacterium avium mostly repressed NF-kappaB activation and only SM and AA could induce its partial activation. While lipids that activate NF-kappaB in uninfected cells tend to kill mycobacteria in macrophages Sph and S1P failed to activate NF-kappaB under most conditions but nevertheless enhanced killing of M. smegmatis, M. avium and M. tuberculosis H37Rv. Our results argue that both NF-kappaB-dependent and -independent mechanisms are involved in macrophage killing of mycobacteria and that both mechanisms can be enhanced by selected lipids.
authors.affiliation: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Postfach 102209, 69117 Heidelberg, Germany. mgutierr@embl.de
authors.forename: Maximiliano Gabriel
authors.initials: MG
authors.lastname: Gutierrez
authors.forename: Alexis Perez
authors.initials: AP
authors.lastname: Gonzalez
authors.forename: Elsa
authors.initials: E
authors.lastname: Anes
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D002460:Cell Line; D007155:Immunologic Factors / Q000494:pharmacology*; D037181:Lectins, C-Type; D008055:Lipids / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D009162:Mycobacterium avium / Q000276:immunology*; D020102:Mycobacterium smegmatis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007155:Immunologic Factors; D037181:Lectins, C-Type; D008055:Lipids; D016328:NF-kappa B; D000099192:CD69 Antigens