THE INTERACTION OF CYTOKINES IN REGULATING ESTRADIOL 17-BETA-HYDROXYSTEROID DEHYDROGENASE-ACTIVITY IN MCF-7 CELLS

Oestradiol 17 beta-hydroxysteroid dehydrogenase (E(2)DH) has a pivotal role in the regulation of oestradiol (E(2)) concentrations in normal and malignant breast tissues. Previous studies have suggested that a n umber of cytokines can stimulate E(2)DH activity to increase the conve rsion of oestrone (E(1)) to E(2). In this investigation we have examin ed the effect of TNF alpha, interleukin-1 beta (IL-1 beta) and IL-6 on E(2)DH activity in MCF-7 breast cancer cells. These cytokines may be produced by breast tumours and their presence in conditioned medium (C M) from tumour-derived fibroblasts was also measured to assess their p ossible contribution to its E(2)DH stimulatory activity. Treatment of MCF-7 cells with IL-1 beta and TNF alpha (5 ng/ml) significantly incre ased (P < 0.001) reductive E(2)DH (red-E(2)DH, the conversion of E(1) to E(2)) activity. In contrast, IL-6 at a concentration of 100 ng/ml p roduced little, if any, stimulation of reductive activity. Combination s of all three cytokines acted synergistically to stimulate red-E(2)DH activity. No cytokine, either alone or in combination, affected oxida tive (E(2)-->E(1)) activity. Significant concentrations of IL-6 and IL -1 beta were detected in CM, but the stimulation of red-E(2)DH activit y was much greater than that which could be explained by their levels alone. It is concluded that these cytokines may play an important role in regulating E(2)DH activity in breast cancer cells and may act syne rgistically in vivo to enhance the formation of E(2) in breast tumours .