Role of lipids in killing mycobacteria by macrophages: evidence for NF-kappaB-dependent and -independent killing induced by different lipids.
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.
Gutierrez
Maximiliano Gabriel
MG
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Postfach 102209, 69117 Heidelberg, Germany. mgutierr@embl.de
Gonzalez
Alexis Perez
AP
Anes
Elsa
E
Griffiths
Gareth
G
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
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007155:Immunologic Factors; D037181:Lectins, C-Type; D008055:Lipids; D016328:NF-kappa B; D000099192:CD69 Antigens