title: A novel IL-25 signaling pathway through STAT5.
abstract: IL-25 is a member of the IL-17 family of cytokines that promotes Th2 cell-mediated inflammatory responses. IL-25 signals through a heterodimeric receptor (IL-25R) composed of IL-17RA and IL-17RB, which recruits the adaptor molecule Act1 for downstream signaling. Although the role of IL-25 in potentiating type 2 inflammation is well characterized by its ability to activate the epithelium as well as T cells, the components of its signaling cascade remain largely unknown. In this study, we found that IL-25 can directly activate STAT5 independently of Act1. Furthermore, conditional STAT5 deletion in T cells or epithelial cells led to a defective IL-25-initiated Th2 polarization as well as defective IL-25 enhancement of Th2 responses. Finally, we found that STAT5 is recruited to the IL-25R in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Together, these findings reveal a novel Act1-independent IL-25 signaling pathway through STAT5 activation.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195;
authors.forename: Jarod A
authors.initials: JA
authors.lastname: Zepp
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Wen
authors.initials: W
authors.lastname: Qian
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Martin
authors.affiliation: Department of Immunology, Genentech, South San Francisco, CA 94080;
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Weiguo
authors.initials: W
authors.lastname: Yin
authors.affiliation: Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta, Atlanta, GA 30329; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; and.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
authors.affiliation: Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.
authors.forename: Mark
authors.initials: M
authors.lastname: Aronica
authors.affiliation: Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.
authors.forename: Serpil
authors.initials: S
authors.lastname: Erzurum
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; lix@ccf.org.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D018123:Receptors, Interleukin / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C541130:ACT1 protein; D018031:Connexin 43; D016207:Cytokines; D007378:Interleukins; D008024:Ligands; C442281:Mydgf protein, mouse; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D050799:STAT5 Transcription Factor
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