Complex interactions between sex steroids and cytokines in the human pregnant myometrium: Evidence for an autocrine signaling system at term

Little is known about the mechanisms controlling the expression of key proteins that regulate excitability and contractility in the human myometrium at term. However, evidence is accumulating to suggest that the cytokine transforming growth factor (TGF)beta may play a central role. TGF beta 1 and TGF beta receptors are present in the myometrial cells, indicative of an autocrine signaling system. Furthermore, the levels of TGF beta 1 and the expression of its receptors increase in the myometrium at term suggesting that they are, in turn, regulated and form part of a physiological cascade of events involving a number of autocrine signaling associated proteins. The present experiments were done to identify factors that regulate the expression of TGF beta 1 and TGF beta receptors and may form other elements of this cascade. Because IL-1 and IL-8 are found in the myometrium at term and have been implicated in the etiology in premature labor we focus on this cytokines. Receptors for IL-1 and IL-8 were detected in the myometrial cells. Using Western blot analysis, the levels of expression were found to vary. The expression of IL-1 receptor type I was highest in the nonpregnant tissue with lower levels in nonlaboring myometrium with a further reduction in the spontaneously laboring tissue. In contrast, the expression of IL-8 receptor type B was highest in the pregnant nonlaboring tissue with a lower level in the spontaneously laboring tissue. Using an in vitro model, TGF beta 1 and TGF beta receptor expression was up-regulated by IL-8, IL-1, and TGF beta 1 itself. However, IL-8 receptor expression was decreased by IL-8 and TGF beta 1. This suggests that in a cascade IL-8 would feed forward to promote the TGF beta system, whereas TGF beta 1 feeds hack to inhibit responsiveness to IL8. Estrogen and progesterone increased the release of TGF beta 1. However, at high concentrations, estrogen and progesterone (100 nM 17 beta-estradiol or 200 nM progesterone) decreased the level of TGF beta receptor expression. Thus, the progressive rise of steroid levels in vivo might account for the observed changes in TGF beta 1 and TGF beta receptor expression in vivo. Taken together, these observations support the idea that there is a cascade of autocrine signals that may play a major role in the physiological processes preparing the myometrium far parturition at term.