A novel IL-25 signaling pathway through STAT5

  • J Immunol. 2015 May 1;194(9):4528-34. doi: 10.4049/jimmunol.1402760.
Ling Wu  1 ,  Jarod A Zepp  2 ,  Wen Qian  3 ,  Bradley N Martin  1 ,  Wenjun Ouyang  4 ,  Weiguo Yin  3 ,  Kevin D Bunting  5 ,  Mark Aronica  6 ,  Serpil Erzurum  6 ,  Xiaoxia Li  7
Affiliations
  • 1. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
  • 2. 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;
  • 3. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;
  • 4. Department of Immunology, Genentech, South San Francisco, CA 94080;
  • 5. 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.
  • 6. Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.
  • 7. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; [email protected].
PMID: 25821217 DOI: 10.4049/jimmunol.1402760
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.