title: IL-12 and IL-27 regulate the phagolysosomal pathway in mycobacteria-infected human macrophages.
abstract: BACKGROUND
  The cytokine environment at the site of infection is important to the control of mycobacteria by host macrophages. During chronic infection immunosuppressive cytokines are likely to favor mycobacterial growth, persistence, and an avoidance of proper antigen processing and presentation. The activity of interleukin (IL)-27 toward macrophages is anti-inflammatory and this compromises control of mycobacteria. Modulation of the cytokine environment may enhance both protective and vaccine-induced responses.
  
  
  RESULTS
  In this study we showed that supplying IL-12 and neutralizing IL-27 enhanced acidification and fusion of mycobacterial-containing phagosomes with lysosomes. This was achieved by phagosomal acquisition of vacuolar ATPase (V-ATPase) and CD63. Both V-ATPase and CD63 protein levels were increased by the addition of IL-12 and neutralization of IL-27. In addition, cathepsin D associated with the bacteria and matured to the active form when IL-12 was supplied and IL-27 was neutralized. Lysosomal acidification and cathepsin D activity were associated with control of mycobacteria. The acidification of lysosomes, association with mycobacteria, and maturation of cathepsin D required macrophage production of IFN-γ and signaling through signal transducer and activator of transcription (STAT)-1. In contrast, STAT-3 signaling opposed these events.
  
  
  CONCLUSIONS
  Our results have identified novel influences of IL-12, IL-27, and STAT-3 on lysosomal activity and further demonstrate that modulating the cytokine environment promotes enhanced trafficking of mycobacteria to lysosomes in human macrophages. This has important implications in approaches to control infection and improve vaccination. Overcoming bacterial resistance to lysosomal fusion may expand the repertoire of antigens presented to the adaptive arm of the immune response.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Jung
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, 29209 Columbia, SC, USA. cory.robinson@uscmed.sc.edu.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Robinson
mesh_terms: D000293:Adolescent; D000328:Adult; D002402:Cathepsin D / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology*; D064094:Interleukin-27 / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D009163:Mycobacterium bovis / Q000472:pathogenicity*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D060149:Tetraspanin 30 / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D064094:Interleukin-27; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D060149:Tetraspanin 30; D018664:Interleukin-12; D007371:Interferon-gamma; D002402:Cathepsin D; D025262:Vacuolar Proton-Translocating ATPases