Opposing Actions of Stat1 and Stat6 on Il-13-induced Up-regulation of Early Growth Response-1 and Platelet-derived Growth Factor Ligands in Pulmonary Fibroblasts.
From: CIIT Centers for Health Research, Research Triangle Park, Durham, NC 27709, USA. jbonner@ciit.org
Journal of immunology (Baltimore, Md. : 1950)
- Publish Date: Sep 2006
- ISSN: 0022-1767
- Volume: 177
- Issue: 6
- Pages: 4141-8
- Medium: Print
- Language: English
- Citation (JAMA): Ingram Jennifer L, Antao-Menezes Aurita, Mangum James B, et al. Opposing Actions of Stat1 and Stat6 on Il-13-induced Up-regulation of Early Growth Response-1 and Platelet-derived Growth Factor Ligands in Pulmonary Fibroblasts.. J. Immunol. Sep 2006;177:4141-8
Abstract
IL-13 is a key cytokine involved in airway remodeling in asthma. We previously reported that IL-13 stimulated the mitogenesis of lung fibroblasts via platelet-derived growth factor (PDGF)-AA. In this report, we show that IL-13 increases PDGF-A and PDGF-C mRNA levels through a dual intracellular cascade that requires coactivation of Stat6 and Stat1 to impact transcriptional regulation of the early growth response (Egr)-1 gene, which then drives PDGF expression. Increased levels of PDGF-AA and PDGF-CC protein were observed in vivo in the airways of IL-13 transgenic mice. IL-13 up-regulated PDGF-A and PDGF-C mRNA levels in lung fibroblasts isolated from three different background strains of mice. However, IL-13-induced PDGF-A and PDGF-C mRNA levels were significantly reduced in Stat6-deficient (Stat6(-/-)) fibroblasts as compared with wild-type Stat6(+/+) fibroblasts. In contrast, IL-13-induced PDGF-A and PDGF-C mRNAs were enhanced in Stat1(-/-) fibroblasts as compared with Stat1(+/+) fibroblasts. IL-13 did not up-regulate PDGF-A or PDGF-C mRNA levels in Egr-1(-/-) fibroblasts. Moreover, IL-13 did not increase Egr-1 mRNA and protein levels in Stat6(-/-) fibroblasts and yet enhanced Egr-1 mRNA and protein levels in Stat1(-/-) fibroblasts. Our findings support the hypothesis that Stat6 and Stat1 exert stimulatory and inhibitory effects on Egr-1 and PDGF ligand mRNA transcription, respectively. This novel mechanism could aid in identifying molecular targets for the treatment of chronic airway remodeling and fibrosis in asthma.
Mesh Headings (Keywords): Animals, Cells, Cultured, Down-Regulation, Early Growth Response Protein 1, Fibroblasts, Humans, Interleukin-13, Ligands, Lung, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Platelet-Derived Growth Factor, RNA, Messenger, Receptors, Platelet-Derived Growth Factor, STAT1 Transcription Factor, STAT6 Transcription Factor, Up-Regulation
Check for Full Text / PubMed Unique Identifier (PMID): 16951379
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