title: IL-27 Suppresses Antimicrobial Activity in Human Leprosy.
abstract: The mechanisms by which intracellular pathogens trigger immunosuppressive pathways are critical for understanding the pathogenesis of microbial infection. One pathway that inhibits host defense responses involves the induction of type I interferons and subsequently IL-10, yet the mechanism by which type I IFN induces IL-10 remains unclear. Our studies of gene expression profiles derived from leprosy skin lesions suggested a link between IL-27 and the IFN-β induced IL-10 pathway. Here, we demonstrate that the IL-27p28 subunit is upregulated following treatment of monocytes with IFN-β and Mycobacterium leprae, the intracellular bacterium that causes leprosy. The ability of IFN-β and M. leprae to induce IL-10 was diminished by IL-27 knockdown. Additionally, treatment of monocytes with recombinant IL-27 was sufficient to induce the production of IL-10. Functionally, IL-27 inhibited the ability of IFN-γ to trigger antimicrobial activity against M. leprae in infected monocytes. At the site of disease, IL-27 was more strongly expressed in skin lesions of patients with progressive lepromatous leprosy, correlating and colocalizing with IFN-β and IL-10 in macrophages. Together, these data provide evidence that in the human cutaneous immune responses to microbial infection, IL-27 contributes to the suppression of host antimicrobial responses.
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Rosane M B
authors.initials: RMB
authors.lastname: Teles
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Kindra M
authors.initials: KM
authors.lastname: Kelly-Scumpia
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil.
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Department of Dermatology, University of Southern California School of Medicine, Los Angeles, California, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.affiliation: Department of Dermatology, University of Southern California School of Medicine, Los Angeles, California, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Ochoa
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, California, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA. Electronic address: rmodlin@mednet.ucla.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism*; D064094:Interleukin-27 / Q000378:metabolism* / Q000494:pharmacology; D015440:Leprosy, Lepromatous / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D023421:Models, Animal; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009166:Mycobacterium leprae / Q000378:metabolism* / Q000472:pathogenicity; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D014162:Transfection
chemical_list: D015415:Biomarkers; D016207:Cytokines; D007166:Immunosuppressive Agents; D064094:Interleukin-27; D034741:RNA, Small Interfering; D016753:Interleukin-10; D016899:Interferon-beta