A novel IL-25 signaling pathway through STAT5

J Immunol. 2015 May 1;194(9):4528-34. doi: 10.4049/jimmunol.1402760. Epub 2015 Mar 27.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Connexin 43 / metabolism
  • Cytokines / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Humans
  • Interleukins / metabolism*
  • Ligands
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Peptide Fragments / metabolism
  • Protein Binding
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-17 / metabolism
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction*
  • Th2 Cells / drug effects
  • Th2 Cells / immunology
  • Th2 Cells / metabolism

Substances

  • ACT1 protein
  • Connexin 43
  • Cytokines
  • Interleukins
  • Ligands
  • Mydgf protein, mouse
  • Peptide Fragments
  • Receptors, Interleukin
  • Receptors, Interleukin-17
  • STAT5 Transcription Factor