title: IL-27R-mediated regulation of IL-17 controls the development of respiratory syncytial virus-associated pathogenesis.
abstract: IL-27 is a heterodimeric cytokine composed of the subunits p28 and Epstein-Barr virus induced gene (EBI)-3 and is known for its effects on T-cell function and differentiation. IL-27 signals through the widely expressed IL-27 receptor (IL-27R), composed of the ligand-specific IL-27Rα chain and gp130. Engagement of the IL-27R activates STAT1 signaling, induces the expression of the type 1 helper T-cell (Th1) cytokine, interferon γ, and suppresses the differentiation of Th2 and Th17 cells. This study investigates the role of IL-27 signaling in respiratory syncytial virus (RSV) infection using IL-27Rα-deficient mice (IL-27rKO). Analysis of lungs from RSV-infected IL-27rKO mice showed exacerbation of mucus secretion compared with wild type, as well as enhanced expression of Muc5ac and Gob5 mRNA, markers of goblet cell metaplasia/hyperplasia. When compared with wild-type mice, RSV-challenged IL-27rKO mice had enhanced expression of Th17-associated cytokine IL-17a and an imbalance between Th1 and Th2 cytokine levels. Neutralization of IL-17 in RSV-infected IL-27rKO mice resulted in a significant decrease in the pulmonary mucus response and inhibition of the Th2-associated cytokines. Interestingly, IL-17 blockage led to an increase in the expression of IL-27 subunits p28 and EBI-3 in the lungs and lymph nodes of RSV-infected mice. Thus, IL-27 functions as a regulatory cytokine during RSV pathogenesis by suppressing the development of Th17 cells, but it also appears to be regulated by IL-17 induced by the virus.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Denise E
authors.initials: DE
authors.lastname: de Almeida Nagata
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Tine
authors.initials: T
authors.lastname: Demoor
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ptaschinski
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Hung-An
authors.initials: HA
authors.lastname: Ting
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Sihyug
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Michelle
authors.initials: M
authors.lastname: Reed
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan. Electronic address: nlukacs@umich.edu.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D055271:Mucin 5AC / Q000235:genetics / Q000276:immunology; D009088:Mucoproteins / Q000235:genetics / Q000276:immunology; D009093:Mucus / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; C499601:Ebi3 protein, mouse; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009088:Mucoproteins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse
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