Interleukin-25 promotes basic fibroblast growth factor expression by human endothelial cells through interaction with IL-17RB, but not IL-17RA
Article first published online: 29 OCT 2012
© 2012 Blackwell Publishing Ltd
Clinical & Experimental Allergy
Volume 42, Issue 11, pages 1604–1614, November 2012
How to Cite
Clinical & Experimental Allergy 2012 (42) 1604–1614., , , , , , , , , , , .
- Issue published online: 29 OCT 2012
- Article first published online: 29 OCT 2012
- Accepted manuscript online: 6 JUL 2012 12:21PM EST
- Manuscript Accepted: 25 JUN 2012
- Manuscript Revised: 1 JUN 2012
- Manuscript Received: 20 OCT 2011
- National Natural Science Foundation of China. Grant Numbers: 81102250, KM201010025002, KM201110025005, PHR20100331, PHR201008382, RPCD201203, 10JL11, 2008ZR03, 20101107110003
- Asthma UK
- Friends of Guy's Hospital
- Department of Health via the National Institute for Health Research
- the. Grant Numbers: 81102250, KM201010025002, KM201110025005, PHR20100331, PHR201008382, RPCD201203, 10JL11, 2008ZR03, 20101107110003
- National Natural Science Foundation of China. Grant Number: 81102250
- Science and Technology Project of the Beijing Municipal Education Commission. Grant Numbers: KM201010025002, KM201110025005
- Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality. Grant Numbers: PHR20100331, PHR201008382
- Foundation of Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders in Capital Medical University. Grant Number: RPCD201203
- Basic-Clinical Cooperation Project in Capital Medical University. Grant Number: 10JL11
- Natural Science Foundation of Capital Medical University. Grant Number: 2008ZR03
- Research Fund for the Doctoral Program of Higher Education of China. Grant Number: 20101107110003
- DANA Foundation
- basic fibroblast growth factor;
- endothelial cells;
- IL-25 receptor;
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.
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).
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.
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.