Role of lipids in killing mycobacteria by macrophages: evidence for NF-κB-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-kappa B is required for mycobacterial killing, we tested the ability of lipids to activate NF-kappa B in uninfected macrophages and those infected with mycobacteria. In uninfected cells, sphingomyelin (SM), phosphatidylinositol-4-phosphate (PIP) and arachidonic acid (AA) enhanced NF-kappa B activation and the cell surface expression of CD69, a macrophage activation marker regulated by NF-kappa B. Sphingosine (Sph), sphingosine-1-phosphate (S1P), diacylglycerol (DAG), eicosapentanoic acid (EPA) and phosphatidyl choline (PC) failed to activate either NF-kappa B or CD69. Ceramide (Cer) activated CD69 expression without activating NF-kappa B. In Mycobacterium smegmatis-infected cells, NF-kappa B was transiently activated in a manner that was enhanced by SM, PIP and AA. In contrast Mycobacterium avium mostly repressed NF-kappa B activation and only SM and AA could induce its partial activation. While lipids that activate NF-kappa B in uninfected cells tend to kill mycobacteria in macrophages Sph and S1P failed to activate NF-kappa B under most conditions but nevertheless enhanced killing of M. smegmatis, M. avium and M. tuberculosis H37Rv. Our results argue that both NF-kappa B-dependent and -independent mechanisms are involved in macrophage killing of mycobacteria and that both mechanisms can be enhanced by selected lipids.