Interleukin-1 alpha and interleukin-6 act additively to inhibit growth of MCF-7 breast cancer cells in vitro.

We studied the effects of interleukin-1 alpha (IL-1) and interleukin-6 (IL-6) on MCF-7 breast cancer cells to determine whether these cytokines act additively/synergistically to alter cell growth and metabolism. We found that IL-1 alone (1000 units/ml) inhibited cell growth to a greater degree (83.8%) than IL-6 alone (29.2%, P < 0.001). The combination of IL-1 + IL-6 caused greater inhibition of growth (92.9%, P < 0.02) than either cytokine alone. The additive effect was dose dependent for both IL-1 and IL-6. IL-1 and IL-6 also antagonized estradiol (10(-9) M) stimulated growth. Antagonism by the combination was greater than for either cytokine alone (P < 0.001). IL-1 or IL-6 alone each down-regulated the estrogen receptor (36.7%, P < 0.01, and 23.2%, P < 0.05, respectively), but the combination IL-1 + IL-6 did not cause a significantly greater effect than IL-1 alone. Neither IL-1 or IL-6 blocked estradiol stimulation of progesterone receptor (PR) synthesis; however, the combination IL-1 + IL-6 increased PR content by 28.4% (P < 0.01). IL-1, but not IL-6, increased secretion of transforming growth factor-beta (TGF-beta) by 2.45-fold over 72 h (P < 0.01). The increase was time dependent (detectable at 24 h) and dose dependent (maximum increase of 5.3-fold, 10,000 units/ml, P < 0.02). IL-1-induced TGF-beta secretion was blocked by estradiol (10(-9) M). Neither cytokine altered secretion of insulin-like growth factor-1. These findings indicate that IL-1 and IL-6 act additively to inhibit growth in the absence or presence of estradiol and modulate the estrogen receptor and progesterone receptor content of these cells. TGF-beta may mediate the effects of IL-1; however, other pathways appear to be required for the additive effects of these cytokines.