title: Dipterinyl calcium pentahydrate inhibits intracellular mycobacterial growth in human monocytes via the C-C chemokine MIP-1β and nitric oxide.
abstract: Tuberculosis remains one of the top three leading causes of morbidity and mortality worldwide, complicated by the emergence of drug-resistant Mycobacterium tuberculosis strains and high rates of HIV coinfection. It is important to develop new antimycobacterial drugs and immunomodulatory therapeutics and compounds that enhance antituberculous immunity. Dipterinyl calcium pentahydrate (DCP), a calcium-complexed pterin compound, has previously been shown to inhibit human breast cancer cells and hepatitis B virus (HBV). DCP inhibitory effects were attributed to induction of apoptosis and/or increased production of interleukin 12 (IL-12) and granulocyte-macrophage colony-stimulating factor (GM-CSF). In this study, we tested the ability of DCP to mediate inhibition of intracellular mycobacteria within human monocytes. DCP treatment of infected monocytes resulted in a significant reduction in viability of intracellular but not extracellular Mycobacterium bovis BCG. The antimicrobial activity of DCP was comparable to that of pyrazinamide (PZA), one of the first-line antituberculosis drugs currently used. DCP potentiated monocyte antimycobacterial activity by induction of the cysteine-cysteine (C-C) chemokine macrophage inflammatory protein 1β (MIP-1β) and inducible nitric oxide synthase 2. Addition of human anti-MIP-1β neutralizing antibody or a specific inhibitor of the l-arginase-nitric oxide pathway (N(G)-monomethyl l-arginine [l-NMMA] monoacetate) reversed the inhibitory effects of DCP on intracellular mycobacterial growth. These findings indicate that DCP induced mycobacterial killing via MIP-1β- and nitric oxide-dependent effects. Hence, DCP acts as an immunoregulatory compound enhancing the antimycobacterial activity of human monocytes.
authors.affiliation: Division of Infectious Diseases, Allergy & Immunology, Edward A. Doisy Research Center, St. Louis University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Isaac G
authors.initials: IG
authors.lastname: Sakala
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Eickhoff
authors.forename: Azra
authors.initials: A
authors.lastname: Blazevic
authors.forename: Phillip
authors.initials: P
authors.lastname: Moheno
authors.forename: Richard F
authors.initials: RF
authors.lastname: Silver
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D054407:Chemokine CCL4 / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology*; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; C066507:CCL4 protein, human; D054407:Chemokine CCL4; D011621:Pteridines; D012333:RNA, Messenger; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II