TGF-beta1 plays a major role in fibrotic diseases including scleroderma. Human fibroblasts from sclerotic lesions display an increased sensitivity to TGF-beta1. Similarly, fibroblasts from TSK mice which develop a scleroderma-like syndrome are hyperresponsive to TGF-beta. The aim of the present study was to investigate whether the TGF-beta hypersensitivity demonstrated by TSK/+ fibroblasts is associated with polymorphisms of the TGF-beta1 promoter. Sequence analysis revealed one polymorphism (a G --> T at -1133 bp) unique to the TSK/+ mouse. Transfection of fibroblasts with a 1.8 kb fragment of the TGF-beta1 promoter containing the -1133 polymorphism exhibited increased basal TGF-beta1 promoter activity which was enhanced upon incubation with TGF-beta1. This may be related to the loss of a negative regulatory site in the TSK/+ TGF-beta1 promoter.