Differential mRNA expression of insulin-like growth factor-1 splice variants in idiopathic pulmonary fibrosis and pulmonary sarcoidosis patients

Bloor, CA; Knight, RA; Kedia, RK; Spiteri, MA; Allen, JT

Abstract

Insulin-like growth factor-1 (IGF-1) is a highly mitogenic polypeptide detectable in human lung. Using competitive reverse transcriptase/polymerase chain reaction (RT-PCR), expression of four IGF-1 transcripts was examined in bronchoalveolar lavage cells (BALC) from normal subjects, idiopathic pulmonary fibrosis (IPF), stage I/II (no fibrosis), and stage III/IV (confirmed fibrosis) pulmonary sarcoidosis patients, and fibroblast strains isolated from normal and IPF lungs. Transcripts studied were Class 1 and Class 2 (exons 1 or 2, respectively) with IGF-1Eb or IGF-1Ea (exons 5 or 6, respectively). Total IGF-1 expression was downregulated in BALC of both patients with IPF (p < 0.01) and patients with sarcoidosis (p < 0.04) compared with healthy subjects. In contrast, both constitutive (p < 0.003) and transforming growth factor-beta (TGF-beta)- induced (p < 0.02) IGF-1 expression was higher in fibrotic, compared with normal, fibroblasts. These changes were associated with differential expression of IGF-1 splice variants. Healthy subjects and sarcoidosis patients without fibrosis showed similar expression of Class 1/Class 2 and IGF-1Ea/IGF-1Eb. However, patients with fibrosis demonstrated discordant, increased relative abundance of Class 1 transcripts (p < 0.01). In parallel, all fibrosis patients failed to express Class 2, IGF-1Eb forms and sarcoidosis patients with fibrosis did not express the Class 1, IGF-1Eb variant either. Fibrotic fibroblasts expressed higher constitutive levels of Class 1, IGF-1Ea transcripts compared with normal fibroblasts. Class 2, IGF-1Eb forms were moderately expressed by fibroblasts only after stimulation with TGF-beta, which also further increased levels of Class 1, IGF-1Ea transcripts. Our findings suggest that transition from a healthy to a fibrotic phenotype occurs in association with a changing pattern of IGF-1 mRNA heterogeneity and leads us to hypothesize a potential role for specific IGF-1 variants in fibrogenesis.

Citation

Bloor, C., Knight, R., Kedia, R., Spiteri, M., & Allen, J. (2001). Differential mRNA expression of insulin-like growth factor-1 splice variants in idiopathic pulmonary fibrosis and pulmonary sarcoidosis patients. American Journal of Respiratory and Critical Care Medicine, 164(2), 265-272

• Journal Article Type: Article
• Publication Date: Jul 1, 2001
• Deposit Date: Aug 7, 2007
• Journal: American Journal of Respiratory and Critical Care Medicine
• Print ISSN: 1073-449X
• Publisher: American Thoracic Society
• Peer Reviewed: Peer Reviewed
• Volume: 164
• Issue: 2
• Pages: 265-272
• Keywords: IGF-1, mRNA transcripts, idiopathic pulmonary fibrosis, pulmonary sarcoidosis, fibroblasts, competitive RT-PCR
• Publisher URL: http://ajrccm.atsjournals.org/cgi/content/abstract/164/2/265