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.
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.
Ingram
Jennifer L
JL
CIIT Centers for Health Research, Research Triangle Park, Durham, NC 27709, USA. jbonner@ciit.org
Antao-Menezes
Aurita
A
Mangum
James B
JB
Lyght
Otis
O
Lee
Patty J
PJ
Elias
Jack A
JA
Bonner
James C
JC
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050800:STAT6 Transcription Factor / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018793:Interleukin-13; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D017479:Receptors, Platelet-Derived Growth Factor