title: IL-10 blocks phagosome maturation in mycobacterium tuberculosis-infected human macrophages.
abstract: Successful phagolysosomal maturation is an important innate immune response to intracellular infection. However, Mycobacterium tuberculosis (Mtb) can manipulate and inhibit this host response to ensure survival within its niche cell. We investigate the role of the anti-inflammatory cytokine IL-10 on Mtb-phagosome maturation. Blocking IL-10, which was secreted from Mtb-infected macrophages, allowed phagosome maturation to proceed. Macrophage cytokine gene expression profiles were not significantly altered by blocking IL-10 3 hours after infection with Mtb. We demonstrate that IL-10 can regulate this protective phenotype in phorbol myristate acetate (PMA)-treated THP-1 cells, monocyte-derived macrophages (MDMs), and human alveolar macrophages (AMs) infected with Mtb. The regulatory effect of endogenous IL-10 was evident in macrophages infected with virulent Mtb H37Rv, as well as in attenuated strains of mycobacteria. Unlike live Mtb, dead bacilli occupy a mature, acidic phagosome. However, the addition of IL-10 to cells infected with killed Mtb successfully inhibited the maturation of this compartment. Importantly, we demonstrate that the addition of IL-10 to MDMs results in enhanced mycobacterial survival and growth. Our results suggest that IL-10 exerts its effects on this early macrophage response in a partly signal transducer and activator of transcription 3 (STAT3)-dependent manner, and independent of mitogen activated protein kinase p38 (MAPKp38) and extracellular regulated kinase 1/2 (ERK1/2) activity. IL-10 is a feature of human tuberculous granuloma, and these new findings support the hypothesis that this cytokine can promote pathogen persistence by contributing to Mtb-phagosome maturation arrest in human macrophages.
authors.affiliation: Respiratory Medicine, St. James's Hospital, CResT, Dublin 8, Ireland.
authors.forename: Seónadh
authors.initials: S
authors.lastname: O'Leary
authors.forename: Mary P
authors.initials: MP
authors.lastname: O'Sullivan
authors.forename: Joseph
authors.initials: J
authors.lastname: Keane
mesh_terms: D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D006099:Granuloma / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014376:Tuberculosis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002273:Carcinogens; C508609:IL10 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate