title: Modulation of innate host factors by Mycobacterium avium complex in human macrophages includes interleukin 17.
abstract: BACKGROUND
  Although opportunistic infections due to Mycobacterium avium complex (MAC) have been less common since the introduction of highly active antiretroviral therapy, globally, human immunodeficiency virus-1 (HIV-1)-positive patients remain predisposed to these infections. Absence of a properly functioning acquired immune response allows MAC persistence within macrophages localized in lymph nodes coinfected with HIV and MAC. Although a deficiency in interferon γ appears to play a part in the ability of MAC to deflect the macrophage-associated antimicrobial attack, questions about this process remain. Our study examines the ability of MAC to regulate interleukin 17 (IL-17), a proinflammatory cytokine involved in host cell recruitment.
  
  
  METHODS
  Coinfected lymph nodes were examined for IL-17 by immunohistochemical analysis. In vitro, macrophages exposed to mycobacteria were evaluated for transcription activities, proteins, and signaling pathways responsible for IL-17 expression. Infected macrophages were also analyzed for expression of interleukin 21 (IL-21) and negative regulators of immune responses.
  
  
  RESULTS
  Infection of macrophages triggered synthesis of IL-17, correlating with IL-17 expression by macrophages in coinfected lymph nodes. Infected macrophages exposed to exogenous IL-17 expressed CXCL10, which favors recruitment of new macrophages as targets for infection. Blockade of nuclear factor κ-light-chain-enhancer of activated B cells and mitogen-activated protein kinase pathways suppressed mycobacteria-induced IL-17 expression. MAC triggered expression of IL-21, IRF4, and STAT3 genes related to IL-17 regulation, as well as expression of the negative immunoregulators CD274(PD-L1) and suppressors of cytokine signaling.
  
  
  CONCLUSIONS
  MAC-infected macrophages can provide an alternative source for IL-17 that favors accumulation of new targets for perpetuating bacterial and viral infection while suppressing host antimicrobial immune responses.
authors.affiliation: Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892-4352, USA. nvazquez@mail.nih.gov
authors.forename: Nancy
authors.initials: N
authors.lastname: Vázquez
authors.forename: Sofia
authors.initials: S
authors.lastname: Rekka
authors.forename: Maria
authors.initials: M
authors.lastname: Gliozzi
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Shoba
authors.initials: S
authors.lastname: Amarnath
authors.forename: Jan M
authors.initials: JM
authors.lastname: Orenstein
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Wahl
mesh_terms: D002478:Cells, Cultured; D060085:Coinfection / Q000276:immunology*; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000150:complications / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D006805:Human Experimentation; D006801:Humans; D057131:Immune Evasion; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology; D008198:Lymph Nodes / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D015269:Mycobacterium avium Complex / Q000276:immunology*; D015270:Mycobacterium avium-intracellulare Infection / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: D020381:Interleukin-17; D007378:Interleukins; D000098546:Interleukin-21