Interleukin-1 stimulates the aromatase activity of human placental cytotrophoblasts.

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Abstract
Interleukin-1 (IL-1) is a multifunctional immunoregulatory peptide. Evidence suggests that IL-1 of either decidual or placental origin may serve a role in the paracrine/autocrine regulation of placental function, and the present studies were conducted to define the effects of IL-1 on the aromatase activity of human placental cytotrophoblasts. When freshly isolated cytotrophoblasts were incubated in medium supplemented with androstenedione, treatment with human IL-1 beta (hIL-1 beta) consistently increased the aromatization of this androgen to estrogens. In a representative experiment, hIL-1 beta (50 ng/ml) increased aromatization at 4 and 24 h by 145% (P < 0.001) and 78% (P < 0.05), respectively. This was indeed due to increased hIL-1 beta-mediated estrogen biosynthesis, rather than to decreased catabolism of estrogens, since cytotrophoblasts incubated in the presence of hIL-1 beta for 24 h exhibited 65% greater aromatase activity than control cells (P < 0.0001), as quantitated by the specific release of 3H2O from [3H] androstenedione. Stimulation of aromatase activity by hIL-1 beta was concentration dependent and saturable, and significant (P < 0.05) stimulation could be demonstrated at a hIL-1 beta concentration as low as 20 ng/ml. In time-course studies, significant stimulation of the conversion of androstenedione to estrogens by hIL-1 beta could be detected as early as after 4 h of treatment and persisted for at least 24 h. Human IL-1 alpha stimulated the conversion of androstenedione to estrogens to an extent similar to that of hIL-1 beta, whereas the effects of murine IL-1 beta on aromatase activity were inconsistent. To determine whether endogenous IL-1 beta produced by cytotrophoblasts could itself act to stimulate aromatase activity, a neutralizing anti-IL-1 beta antibody was employed. When cells were incubated in the presence of anti-IL-1 beta antibody for either 4 or 24 h, the conversion of androstenedione to estrogens was significantly decreased compared to that in control incubations, whereas aromatase activity was not altered by the addition of nonimmune rabbit immunoglobulin G. These findings suggest that 1) both hIL-1 beta and hIL-1 alpha stimulate the aromatase activity of human cytotrophoblasts; and 2) endogenously produced IL-1 beta may function physiologically to enhance cytotrophoblastic aromatase activity.

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