title: T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma.
abstract: IL-25 (IL-17E) is a T-helper cell type 2 (Th2) cytokine best described as a potentiator of Th2 memory responses. Reports of expression of its receptor, IL-25R, on airways structural cells suggest a wider role for IL-25 in remodeling. We hypothesized that IL-25 stimulates local angiogenesis in the asthmatic bronchial mucosa. Immunoreactive IL-25(+), IL-25R(+), and CD31(+) (endothelial) cells in sections of bronchial biopsies from asthmatics and controls were detected by immunohistochemistry. The effect of IL-25 on angiogenesis was examined using an in vitro assay. Real-time PCR was used to detect expression of IL-25R and VEGF mRNA in cultured human vascular endothelial cells (HUVEC), and a cell proliferation kit (WST-8) was used to measure the effect of IL-25 on HUVEC proliferation. Immunostaining showed that IL-25(+), IL-25R(+), and CD31(+)/IL-25R(+) cells were significantly elevated in the bronchial mucosa of asthmatics compared with controls (P < 0.003). In asthmatics, the numbers of IL-25(+) cells correlated inversely with the forced expiratory volume in 1 s (r = -0.639; P = 0.01). In vitro, HUVEC constitutively expressed IL-25R, which was up-regulated further by TNF-α. IL-25 and TNF-α also increased expression of VEGF and VEGF receptors. IL-25 increased HUVEC proliferation and the number, length, and area of microvessel structures in a concentration-dependent manner in vitro. VEGF blockade, the PI3K-specific inhibitor LY294002, and the MAPK/ERK1/2 (MEK1/2)-specific inhibitor U0126 all markedly attenuated IL-25-induced angiogenesis, and the inhibitors also reduced IL-25-induced proliferation and VEGF expression. Our findings suggest that IL-25 is elevated in asthma and contributes to angiogenesis, at least partly by increasing endothelial cell VEGF/VEGF receptor expression through PI3K/Akt and Erk/MAPK pathways.
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London, Medical Research Council, and Asthma UK Centre in Allergic Mechanisms of Asthma, London SE1 9RT, United Kingdom.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Corrigan
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Qiu
authors.initials: Q
authors.lastname: Meng
authors.forename: Cailong
authors.initials: C
authors.lastname: Fang
authors.forename: Huifen
authors.initials: H
authors.lastname: Wu
authors.forename: Victoria
authors.initials: V
authors.lastname: Reay
authors.forename: Ze
authors.initials: Z
authors.lastname: Lv
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Fan
authors.forename: Yunqing
authors.initials: Y
authors.lastname: An
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Tak H
authors.initials: TH
authors.lastname: Lee
authors.forename: Sun
authors.initials: S
authors.lastname: Ying
mesh_terms: D000328:Adult; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D015153:Blotting, Western; D001980:Bronchi / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C486701:IL25 protein, human; D020381:Interleukin-17; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018123:Receptors, Interleukin; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases