title: IL-27p28 inhibits central nervous system autoimmunity by concurrently antagonizing Th1 and Th17 responses.
abstract: Central nervous system (CNS) autoimmunity such as uveitis and multiple sclerosis is accompanied by Th1 and Th17 responses. In their corresponding animal models, experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE), both responses are induced and can drive disease independently. Because immune responses have inherent plasticity, therapeutic targeting of only one pathway could promote the other, without reducing pathology. IL-27p28 antagonizes gp130, required for signaling by IL-27 and IL-6, which respectively promote Th1 and Th17 responses. We therefore examined its ability to protect the CNS by concurrently targeting both effector responses. Overexpression of IL-27p28 in vivo ameliorated EAU as well as EAE pathology and reduced tissue infiltration by Th1 and Th17 cells in a disease prevention, as well as in a disease reversal protocol. Mechanistic studies revealed inhibition of Th1 and Th17 commitment in vitro and decreased lineage stability of pre-formed effectors in vivo, with reduction in expression of gp130-dependent transcription factors and cytokines. Importantly, IL-27p28 inhibited polarization of human T cells to the Th1 and Th17 effector pathways. The ability of IL-27p28 to inhibit generation as well as function of pathogenic Th1 and Th17 effector cells has therapeutic implications for controlling immunologically complex autoimmune diseases.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Wai Po
authors.initials: WP
authors.lastname: Chong
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Reiko
authors.initials: R
authors.lastname: Horai
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Mattapallil
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Phyllis B
authors.initials: PB
authors.lastname: Silver
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Ru
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sergeev
authors.affiliation: Flow Cytometry Core Facility, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Villasmil
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-1857, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D019070:Cell Lineage / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: C486767:Il27 protein, mouse; D015850:Interleukin-6; D007378:Interleukins; D014157:Transcription Factors
keywords: Autoimmunity; IL-27p28; gp130
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