期刊
CLINICAL AND EXPERIMENTAL ALLERGY
卷 42, 期 11, 页码 1604-1614出版社
WILEY
DOI: 10.1111/j.1365-2222.2012.04062.x
关键词
basic fibroblast growth factor; endothelial cells; IL-25; IL-25 receptor; remodelling
资金
- National Natural Science Foundation of China [81102250]
- Science and Technology Project of the Beijing Municipal Education Commission [KM201010025002, KM201110025005]
- Project for Academic Human Resources Development in Institutions of Higher Learning Under Jurisdiction of Beijing Municipality [PHR20100331, PHR201 008382]
- Foundation of Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders in Capital Medical University [RPCD201203]
- Basic-Clinical Cooperation Project in Capital Medical University [10JL11]
- Natural Science Foundation of Capital Medical University, Beijing, P.R. China [2008ZR03]
- Research Fund for the Doctoral Program of Higher Education of China [20101107110003]
- DANA Foundation, Asthma UK
- Friends of Guy's Hospital, London, UK
- Department of Health via National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award
- King's College London
- King's College Hospital NHS Foundation Trust
- Medical Research Council [G1000758, G1000758B] Funding Source: researchfish
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 and Clinical Relevance 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.
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