IL-4 UP-REGULATES TENASCIN SYNTHESIS IN SCLERODERMA AND HEALTHY SKIN FIBROBLASTS

Tenascin (TN), a large extracellular matrix glycoprotein, is transient ly expressed during embryonic development, but is absent from most nor mal adult tissues, TN is reexpressed, however, in healing wounds, in t he stroma of some tumors, and in fibrotic diseases such as systemic sc lerosis (SSc) and rheumatoid arthritis, To clarify the mechanisms regu lating TN expression, we studied the effects of selected cytokines (PD GF, 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 strong ly induced TN protein levels (up to 10-fold over the basal level), whe reas PDGF and bFGF were less potent inducers of TN than IL-4, All othe r cytokines tested, including TGF-beta, 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 represso r protein(s) may regulate transcription of the TN gene, Although no di fferences in constitutive TN expression or effects of cytokines on TN expression were observed between SSc and healthy fibroblasts, these da ta 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 re sults suggest that the high level of TN found in the affected tissue o f patients with SSc results from the high level of IL-4 present.