Systemic sclerosis (SSc) is an autoimmune connective tissue disease of unknown etiology in which aberrant fibroblast function results in fibrosis of the skin and internal organs. A distinguishing feature of dermal fibroblasts cultured from SSc lesions is that they produce constitutively, i.e., without exogenous stimulation, as much as 30-fold more interleukin-6 (IL-6) than do normal fibroblasts. The present study indicates that the mechanism of constitutive IL-6 secretion involves the accumulation of IL-6 mRNA in affected SSc fibroblasts, mediated by the constitutive binding of nuclear factors to the IL-6 promoter. DNA-protein complexes formed using nuclear extracts of constitutively expressing cells are distinct from those using extracts of normal cells, with or without exogenous stimulation of IL-6; thus, the mechanisms which regulate constitutive and inducible IL-6 gene expression are apparently distinct. The data also demonstrate that dermal fibroblasts respond very rapidly to IL-6 by increasing expression of the IL-6 gene, thus suggesting a mechanism for the establishment and/or persistence of constitutive expression. The constitutive secretion of IL-6 may play an important role in the perpetuation of the local immune dysregulation and fibroblast activation in the SSc lesion.