title: Metabolism of nitric oxide by Neisseria meningitidis modifies release of NO-regulated cytokines and chemokines by human macrophages.
abstract: Macrophages produce nitric oxide (NO) via the inducible nitric oxide synthase as part of a successful response to infection. The gene norB of Neisseria meningitidis encodes a NO reductase which enables utilization and consumption of NO during microaerobic respiration and confers resistance to nitrosative stress-related killing by human monocyte-derived macrophages (MDM). In this study we confirmed that NO regulates cytokine and chemokine release by resting MDM: accumulation of TNF-alpha, IL-12, IL-10, CCL5 (RANTES) and CXCL8 (IL-8) in MDM supernatants was significantly modified by the NO-donor S-nitroso-N-penicillamine (SNAP). Using a protein array, infection of MDM with N. meningitidis was shown to be associated with secretion of a wide range of cytokines and chemokines. To test whether NO metabolism by N. meningitidis modifies release of NO-regulated cytokines, we infected MDM with wild-type organisms and an isogenic norB strain. Resulting expression of the cytokines TNF-alpha and IL-12, and the chemokine CXCL8 was increased and production of the cytokine IL-10 and the chemokine CCL5 was decreased in norB-infected MDM, in comparison to wild-type. Addition of SNAP to cultures infected with wild-type mimicked the effect observed in cultures infected with the norB mutant. In conclusion, NorB-catalysed removal of NO modifies cellular release of NO-regulated cytokines and chemokines.
authors.affiliation: Academic Unit of Infection and Immunity, School of Medicine and Biomedical Sciences, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2RX, UK. t.stevanin@sheffield.ac.uk
authors.forename: Tânia M
authors.initials: TM
authors.lastname: Stevanin
authors.forename: Jay R
authors.initials: JR
authors.lastname: Laver
authors.forename: Robert K
authors.initials: RK
authors.lastname: Poole
authors.forename: James W B
authors.initials: JW
authors.lastname: Moir
authors.forename: Robert C
authors.initials: RC
authors.lastname: Read
mesh_terms: D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology*; D009345:Neisseria meningitidis / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009572:Nitrite Reductases / Q000235:genetics / Q000378:metabolism; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010587:Phagocytosis
chemical_list: D018925:Chemokines; D016207:Cytokines; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D009569:Nitric Oxide; D009572:Nitrite Reductases; D010396:Penicillamine