IL-13 and IL-1beta promote lung fibroblast growth through coordinated up-regulation of PDGF-AA and PDGF-Ralpha.
Peribronchiolar fibrosis is a prominent feature of airway remodeling in asthma and involves fibroblast growth and collagen deposition. Interleukin-13 (IL-13), a T-helper 2 cytokine, is a key mediator of airway remodeling in asthma, yet the mechanism through which IL-13 promotes fibroblast growth has not been investigated. In this study, we show that IL-13 stimulates the mitogenesis of mouse, rat, and human lung fibroblasts through release of a soluble mitogen that we identified as PDGF-AA. The IL-13-induced growth of human lung fibroblasts was attenuated by an anti-PDGF-AA neutralizing antibody, and IL-13 stimulated human lung fibroblasts to secrete PDGF-AA. Fibroblasts derived from mouse embryos possessing the lethal Patch mutation, which lack the PDGF-Ralpha, showed no mitogenic response to IL-13. However, Patch cells did exhibit IL-13-induced STAT-6 phosphorylation. Stable transfection of the PDGF-Ralpha into Patch cells restored the growth response to PDGF-AA and IL-13. Through the use of lung fibroblasts from STAT-6-deficient mice, we showed that IL-13-induced PDGF-AA release is STAT-6 dependent, but PDGF-AA-induced growth is STAT-6 independent. Finally, we showed that IL-1beta enhanced IL-13-induced mitogenesis of rat lung fibroblasts through up-regulation of the PDGF-Ralpha. Our findings indicate that IL-13 acts in synergy with IL-1beta to stimulate growth by coordinately up-regulating PDGF-AA and the PDGF-Ralpha, respectively.
Ingram
Jennifer L
JL
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Rice
Annette B
AB
Geisenhoffer
Kristen
K
Madtes
David K
DK
Bonner
James C
JC
D000818:Animals; D000077214:Becaplermin; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D018793:Interleukin-13 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000172:deficiency
D017077:Culture Media, Conditioned; D007375:Interleukin-1; D018793:Interleukin-13; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha