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Published ahead of print on October 6, 2005, doi:10.1165/rcmb.2005-0147OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 213-218, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0147OC

Interleukin-13 and Interleukin-4 Induce Vascular Endothelial Growth Factor Release from Airway Smooth Muscle Cells

Role of Vascular Endothelial Growth Factor Genotype

Débora S. Faffe, Lesley Flynt, Kerri Bourgeois, Reynold A. Panettieri, Jr. and Stephanie A. Shore

Physiology Program, Harvard School of Public Health, Boston, Massachusetts; Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Stephanie Shore, Ph.D., Physiology Program, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail: sshore{at}hsph.harvard.edu

Th2 cytokines induce the release of vascular endothelial growth factor (VEGF) from cultured human airway smooth muscle cells. The objective of this study was to examine the mechanistic basis for IL-4– and IL-13–induced VEGF release and to determine whether genetic differences are responsible for donor-to-donor variability in VEGF release. We measured VEGF mRNA expression by real-time PCR, mRNA stability using actinomycin D, and promoter activity with a VEGF-promoter luciferase reporter construct. We measured IL-4– and IL-13–induced VEGF release in cells from 21 donors by ELISA, genotyped the cells for common single nucleotide polymorphisms in the IL-4R{alpha} (Ile50Val, Ser478Pro, and Gln551Arg) and VEGF (–460T/C, –160C/T, –152G/A, +405C/G and +936 C/T) genes, and stratified the data by IL-4R{alpha} and VEGF genotype. IL-4 and IL-13 increased VEGF release and VEGF mRNA expression. IL-4 also increased mRNA stability but did not affect VEGF promoter activity. There was marked donor-to-donor variability in VEGF release from smooth muscle cells. The presence of Val50, Pro478/Arg551, or the Val50/Pro478/Arg551 IL-4R{alpha} haplotype had little effect on VEGF release. VEGF genotype at +405 or +936 alone had no effect on VEGF release, whereas cells bearing at least one –460C/–152A/+405G VEGF allele had lower release of VEGF in response to IL-13 or IL-4 than cells with other genotypes. Our data suggest that IL-4 and IL-13 mediate their effects on VEGF expression post-transcriptionally and indicate that polymorphisms in the VEGF, but not the IL-4R{alpha}, gene affect VEGF release from smooth muscle cells.

Key Words: asthma • IL-4R{alpha} • polymorphism • TNF{alpha} • mRNA stability




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