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Published ahead of print on October 6, 2005, doi:10.1165/rcmb.2005-0147OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 2, February 2006, 213-218

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Submitted on April 19, 2005
Revised on October 5, 2005

IL-13 and IL-4 Induce VEGF Release from Airway Smooth Muscle Cells: Role of VEGF Genotype

Debora S Faffe1, Lesley Flynt2, Kerri Bourgeois2, Reynold A Panettieri, Jr.3, and Stephanie A Shore2*

1 Physiology Program, Harvard School of Public Health, Boston, MA, USA; Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil, 2 Physiology Program, Harvard School of Public Health, Boston, MA, USA, 3 Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: sshore{at}hsph.harvard.edu.

Rationale: Th2 cytokines induce release of vascular endothelial growth factor (VEGF) from cultured human airway smooth muscle cells. Objective: 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. Methods: 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. Measurements and Main Results: 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. 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. Conclusions: 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, impact VEGF release from smooth muscle cells.




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