TUMOR-NECROSIS-FACTOR-ALPHA, INTERFERON-GAMMA AND DEXAMETHASONE REGULATE IGF-I-MAINTAINED COLLAGEN PRODUCTION IN CULTURED HUMAN FIBROBLASTS

We examined the effects of tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) on the production of collagen by human infant foreskin fibroblasts. Collagen synthesis was maintained in the presence of IGF-I so that cytokine effects could be examined in the absence of serum. TNF alpha inhibited IGF-I-maintained collagen production in a dose-dependent manner. Maximal suppression of 50% was attained at a concentration of 7.5 ng/ml. IFN gamma also suppressed collagen accumulation in IGF-I-maintained cells, with a maximal inhibition to 55% at 375 U/ml. The rate of collagen formation relative to total protein production for secreted proteins was calculated. This value decreased from 10.3% for IGF-I-cultured cells to 6.2% and 8.4% with the inclusion of TNF alpha and IFN gamma respectively, indicating that inhibition was selective for collagen. TNF alpha (5 ng/ml) and IFN gamma (250 U/ml) together suppressed IGF-I-maintained collagen production to approximately 35%, with a decrease from 10.3% to 2.9% in collagen production relative to total protein. The inclusion of a serum-free period prior to the addition of TNF alpha to the cultures resulted in a further inhibition to 15% of control. This increase in inhibition was not seen if dexamethasone was present in the serum-fi-ee period prior to cytokine addition. These data showed that IGF-I-maintained collagen formation is suppressed by the proinflammatory cytokines TNF alpha and IFN gamma, and that these interactions are influenced by dexamethasone. Proinflammatory cytokines interact in a complex manner with other serum factors to modulate IGF-I-stimulated extracellular matrix production and may have important roles in regulating tissue repair.