title: Interleukin-25 promotes basic fibroblast growth factor expression by human endothelial cells through interaction with IL-17RB, but not IL-17RA.
abstract: BACKGROUND
  Unlike other IL-17 family members, the Th2-derived cytokine IL-25 (IL-17E) induces (promotes) Th2 responses. One or both of the two receptors for IL-25 (IL-17RA, IL-17RB) is expressed on inflammatory cells and tissue structural cells, suggesting that in addition to promoting Th2-type inflammation IL-25 may also act on structural cells at sites of Th2-type inflammation such as in the asthmatic bronchial mucosa to promote remodelling changes.
  
  
  OBJECTIVE
  Our previous studies showed elevated expression of IL-25 and IL-17RB immunoreactivity in asthmatic airways with co-localization of the latter to endothelial cells. We therefore hypothesized that IL-25 acts on endothelial cells through this receptor to induce production of the key angiogenic and remodelling cytokine basic fibroblast growth factor (bFGF).
  
  
  METHODS
  Polymerase chain reaction (PCR) immunocytochemistry/immunohistochemistry and ELISA were employed to detect expression of IL-17RB, IL-17RA and bFGF by human vascular endothelial cells (HUVEC) and immunoreactivity for IL-25 and bFGF in asthmatic bronchial biopsies. Receptor-blocking antibodies, PCR and an in vitro angiogenesis assay were used to investigate whether IL-25 acts on IL-17RB or IL-17RA to induce bFGF expression and angiogenesis. PCR was also employed to investigate the signalling pathways involved in IL-25-mediated bFGF expression.
  
  
  RESULTS
  HUVEC constitutively expressed IL-17RB, IL-17RA and bFGF. Production of the latter was further increased by IL-25, but attenuated after blockade of the IL-17RB, but not the IL-17RA receptor. Neutralization of endogenous VEGF and bFGF completely abrogated IL-25-induced angiogenesis which was also inhibited by blocking IL-17RB, but not IL-17RA. The PI3K-specific inhibitor LY294002 also completely attenuated IL-25-induced bFGF expression. Immunoreactivity for IL-25 and bFGF was elevated in the asthmatic bronchial mucosa and the expression of each correlated with the other.
  
  
  CONCLUSIONS
  Our data support the hypothesis that IL-25 contributes to elevated bFGF in asthmatic airways by acting on the endothelial cell IL-17RB receptor through PI3K-signalling pathways. Targeting the pathways might benefit therapy of airways remodelling.
authors.affiliation: Department of Immunology, Capital Medical University, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Fan
authors.forename: Z
authors.initials: Z
authors.lastname: Lv
authors.forename: X J
authors.initials: XJ
authors.lastname: Yao
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: K W
authors.initials: KW
authors.lastname: Huang
authors.forename: Q
authors.initials: Q
authors.lastname: Meng
authors.forename: C L
authors.initials: CL
authors.lastname: Fang
authors.forename: T H
authors.initials: TH
authors.lastname: Lee
authors.forename: C J
authors.initials: CJ
authors.lastname: Corrigan
authors.forename: Y Q
authors.initials: YQ
authors.lastname: An
authors.forename: S
authors.initials: S
authors.lastname: Ying
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D016222:Fibroblast Growth Factor 2