title: The hydroxy-naphthoquinone lapachol arrests mycobacterial growth and immunomodulates host macrophages.
abstract: The present study reports the anti-mycobacterial activity of 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (lapachol) as well as its influence on macrophage functions. Lapachol (L) did not induce apoptosis/necrosis of THP-1 macrophages at ≤32 μg/mL. Mycobacterium avium liquid growth was arrested by ≥32 μg/mL and intra-macrophage proliferation by ≥16 μg/mL lapachol. The main immuno-modulatory effects of lapachol observed were an up-regulation of interferon-γ-receptor 1 (IFN-γR1) and major histocompatibility complex class II (MHCII) surface expression, and a marked inhibition of IL-10 secretion. Lapachol did not affect resting, IFN-γ- or toll-like receptor 2 (TLR2)-induced levels of oxygen and nitrogen metabolism key proteins nor the TLR2-mediated secretion of TNF-α, nor induced either oxidative or endoplasmic reticulum (ER) stress. Lapachol inhibited the surface expression of the co-stimulatory molecule CD86 but not that of CD80 and CD83. The results obtained indicate that the substituted naphthoquinone lapachol exhibits an anti-mycobacterial activity that is more efficient intra- than extra-cellularly, and exerts immuno-modulatory effects some of which may enhance the capacity of the host cell to control mycobacterial growth. The immune-modulatory action of lapachol could contribute to its more efficient intra-macrophage anti-mycobacterial activity.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
authors.forename: Renato A S
authors.initials: RA
authors.lastname: Oliveira
authors.forename: Eulalia
authors.initials: E
authors.lastname: Azevedo-Ximenes
authors.forename: Roberto
authors.initials: R
authors.lastname: Luzzati
authors.forename: Rodolfo C
authors.initials: RC
authors.lastname: Garcia
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D018122:B7-1 Antigen / Q000032:analysis / Q000276:immunology; D051940:B7-2 Antigen / Q000032:analysis / Q000276:immunology; D002460:Cell Line; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D056747:Immunomodulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000276:immunology; D009162:Mycobacterium avium / Q000187:drug effects*; D009285:Naphthoquinones / Q000494:pharmacology*; D009584:Nitrogen / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D010100:Oxygen / Q000378:metabolism; D017471:Receptors, Interferon / Q000032:analysis / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000032:analysis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000096743:Interferon gamma Receptor; D000097802:CD83 Antigen
chemical_list: D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D007155:Immunologic Factors; D007371:Interferon-gamma; D016753:Interleukin-10; D008562:Membrane Glycoproteins; D009285:Naphthoquinones; D009584:Nitrogen; D010100:Oxygen; D017471:Receptors, Interferon; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; D000097802:CD83 Antigen; C495342:TLR2 protein, human; C008252:lapachol