MAXIMAL PDGF-INDUCED LUNG FIBROBLAST CHEMOTAXIS REQUIRES PDGF RECEPTOR-ALPHA

Alteration of the platelet-derived growth factor (PDGF) receptor syste m could be important in enhancing the mitogenic and chemotactic potent ial of lung fibroblasts during pulmonary fibrogenesis. We previously r eported that interleukin-1 beta (IL-1 beta) upregulates the PDGF recep tor-alpha (PDGFR-alpha) gene, and in this study we sought to establish the importance of the PDGFR-alpha relative to the PDGFR-beta in media ting a chemotactic reponse to PDGF-AA, -AB, and -BB. Pretreatment of f ibroblasts for 24 h with IL-1 beta increased chemotaxis to all three P DGF isoforms. IL-1 beta pretreatment markedly increased the maximal nu mber of I-125-labeled PDGF-AA binding sites but did not change the num ber of I-125-PDGF-AB or PDGF-BB sites. However, IL-1 beta increased I- 125-PDGF-AB affinity twofold. Neomycin (5 mM) was used as a PDGFR-alph a antagonist and completely blocked I-125-PDGF-AA binding and PDGF-AA- induced chemotaxis. The binding affinity of I-125-PDGF-AB and I-125-PD GF-BB was increased two- to threefold by neomycin, and chemotaxis to P DGF-AB and PDGF-BB was enhanced. These results define a role for the P DGFR-alpha as a regulatory receptor subtype that is necessary for PDGF isoforms to exert maximal chemotaxis.