Tenascin (TN), a large extracellular matrix glycoprotein, is transiently expressed during embryonic development, but is absent from most normal adult tissues. TN is reexpressed, however, in healing wounds, in the stroma of some tumors, and in fibrotic diseases such as systemic sclerosis (SSc) and rheumatoid arthritis. To clarify the mechanisms regulating TN expression, we studied the effects of selected cytokines (PDGF, bFGF, TGF-beta, IL-1, IL-4, IL-6, IFN-gamma, and TNF-alpha) found in fibrotic tissue on TN expression by dermal fibroblasts. IL-4 strongly induced TN protein levels (up to 10-fold over the basal level), whereas PDGF and bFGF were less potent inducers of TN than IL-4. All other cytokines tested, including TGF-alpha1, did not stimulate TN synthesis. IL-4 also increased TN mRNA expression, and this effect was blocked by actinomycin D. Cycloheximide increased basal TN mRNA expression and induced TN mRNA in IL-4-treated fibroblasts, suggesting that repressor protein(s) may regulate transcription of the TN gene. Although no differences in constitutive TN expression or effects of cytokines on TN expression were observed between SSc and healthy fibroblasts, these data are consistent with the observations that high levels of both IL-4 and TN are present in the affected skin of patients with SSc. These results suggest that the high level of TN found in the affected tissue of patients with SSc results from the high level of IL-4 present.