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* CIIT Centers for Health Research, Research Triangle Park, Durham, NC 27709; and
Yale University School of Medicine, New Haven, CT 06520
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by the Long-Range Research Initiative of the American Chemistry Council provided to CIIT Centers for Health Research.
2 Address correspondence and reprint requests to Dr. James C. Bonner, CIIT Centers for Health Research, P.O. Box 12137 Research Triangle Park, Durham, NC 27709; E-mail address: jbonner{at}ciit.org or at the current address: Dr. Jennifer L. Ingram, Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710; E-mail address: jennifer.ingram{at}duke.edu
3 Abbreviations used in this paper: PDGF, platelet-derived growth factor; Egr-1, early growth response-1 gene; SOCS, suppressor of cytokine signaling.
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