Alteration of the platelet-derived growth factor (PDGF) receptor system could be important in enhancing the mitogenic and chemotactic potential of lung fibroblasts during pulmonary fibrogenesis. We previously reported that interleukin-1 beta (IL-1 beta) upregulates the PDGF receptor-alpha (PDGFR-alpha) gene, and in this study we sought to establish the importance of the PDGFR-alpha relative to the PDGFR-beta in mediating a chemotactic response to PDGF-AA, -AB, and -BB. Pretreatment of fibroblasts for 24 h with IL-1 beta increased chemotaxis to all three PDGF isoforms. IL-1 beta pretreatment markedly increased the maximal number of 125I-labeled PDGF-AA binding sites but did not change the number of 125I-PDGF-AB or PDGF-BB sites. However, IL-1 beta increased 125I-PDGFR-AB affinity twofold. Neomycin (5 mM) was used as a PDGFR-alpha antagonist and completely blocked 125I-PDGF-AA binding and PDGF-AA-induced chemotaxis. The binding affinity of 125I-PDGF-AB and 125I-PDGF-BB was increased two-to threefold by neomycin, and chemotaxis to PDGF-AB and PDGF-BB was enhanced. These results define a role for the PDGFR-alpha as a regulatory receptor subtype that is necessary for PDGF isoforms to exert maximal chemotaxis.