title: Transcriptional suppression of IL-27 production by Mycobacterium tuberculosis-activated p38 MAPK via inhibition of AP-1 binding.
abstract: Mycobacterium tuberculosis remains a major global challenge to human health care, and the mechanisms of how M. tuberculosis evades host immune surveillance to favor its survival are still largely unknown. In this study, we found that bacillus Calmette-Guérin (BCG) and viable M. tuberculosis as well as M. tuberculosis lysates could activate IL-27 expression in human and mouse macrophages by induction of p28 subunit transcription. However, in parallel with these effects, BCG and M. tuberculosis lysate stimulation of macrophages induced activation of p38 MAPK signaling molecules MLK3/MKK3/MK2 to prevent maximal IL-27 production. M. tuberculosis lysate-induced p28 transcription was dependent on MyD88 signaling pathway. AP-1/c-Fos was shown to bind directly to the p28 promoter and induce p28 expression after M. tuberculosis lysate stimulation. Overexpression of p38α inhibited the binding of c-Fos to the p28 promoter but had no effect on c-Fos protein expression or phosphorylation in response to M. tuberculosis lysate stimulation. Furthermore, blockade of p38 by SB203580 enhanced M. tuberculosis-induced AP-1 binding to the p28 promoter. Importantly, we show that adding exogenous IL-27 to increase the levels produced by PBMCs stimulated with live mycobacteria enhanced the ability of BCG-expanded T cells to inhibit intracellular mycobacterial growth in human macrophages. Taken together, our data demonstrate that mycobacterial stimulation induces both IL-27 production and p38 MAPK activation. Strategies designed to tip the balance toward positive regulation of p28 induction by mycobacteria could lead to enhanced protective tuberculosis immunity.
authors.affiliation: Division of Infectious Diseases, Allergy, and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.forename: Xuesong
authors.initials: X
authors.lastname: Qian
authors.forename: Huan
authors.initials: H
authors.lastname: Ning
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Eickhoff
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hoft
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics*; D007378:Interleukins / Q000235:genetics; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics; D009163:Mycobacterium bovis / Q000276:immunology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C486767:Il27 protein, mouse; D007093:Imidazoles; D020381:Interleukin-17; D007378:Interleukins; D053594:Myeloid Differentiation Factor 88; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D018808:Transcription Factor AP-1; D048308:Mitogen-Activated Protein Kinase 14; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580