Interferons gamma and alpha-2b differentially regulate the expression of collagenase and tissue inhibitor of metalloproteinase-1 messenger RNA in human hypertrophic and normal dermal fibroblasts.

We have recently shown that both interferon gamma (gamma) and interferon alpha-2b (alpha-2b) markedly depress the expression of messenger RNA for type I procollagen and fibronectin in postburn hypertrophic scar and normal dermal fibroblasts. In this article we examine the effects of these cytokines on the expression of mRNA for collagenase and its natural inhibitor, tissue inhibitor of metalloproteinase-1. Twelve different fibroblast cell strains, six from postburn hypertrophic scar and six from the normal dermis of the same patients, were established in cell culture. The results of a dose response experiment showed increases in collagenase mRNA up to 4000 U/ml of interferon-alpha-2b, but maximal increases in tissue inhibitor of metalloproteinase mRNA expression and maximal decrease in mRNA for type I procollagen at 2000 U/ml. For subsequent experiments cells were treated with either interferon-alpha-2b (2000 U/ml) or -gamma (1000 U/ml) for 96 hours. Quantitative analysis showed increases in tissue inhibitor of metalloproteinase-1 and collagenase mRNA (81% and 54%, respectively) in interferon-alpha-2b-treated hypertrophic scar fibroblasts. Under the same experimental conditions, interferon-alpha-2b had similar effects on normal dermal fibroblasts; however, interferon-gamma had a differential effect on the expression of mRNA for collagenase and tissue inhibitor of metalloproteinase-1. Cells treated with interferon-gamma showed increases in tissue inhibitor of metalloproteinase-1 mRNA (78% in hypertrophic scar and 56% in normal dermal fibroblasts) but decreases (59% and 42%, respectively) in collagenase mRNA. These effects appear to be selective because rehybridization of blots with a complementary DNA for tissue inhibitor of metalloproteinase-2 mRNA showed no marked alteration in the abundance of this transcript. Significantly greater collagenase activity was found in conditioned medium from interferon-alpha-2b-treated hypertrophic scar cells compared with that from interferon-gamma-treated cells. These findings suggest that interferon alpha-2b would have some advantages over interferon-gamma for the treatment of dermal fibroproliferative disorders, such as postburn hypertrophic scar.