Complex Interactions Between Sex Steroids and Cytokines in the Human Pregnant Myometrium: Evidence for an Autocrine Signaling System at Term

Abstract

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. TGFbeta1 and TGFbeta receptors are present in the myometrial cells, indicative of an autocrine signaling system. Furthermore, the levels of TGFbeta1 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 TGFbeta1 and TGFbeta 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, TGFbeta1 and TGFbeta receptor expression was up-regulated by IL-8, IL-1, and TGFbeta1 itself. However, IL-8 receptor expression was decreased by IL-8 and TGFbeta1. This suggests that in a cascade IL-8 would feed forward to promote the TGFbeta system, whereas TGFbeta1 feeds back to inhibit responsiveness to IL-8. Estrogen and progesterone increased the release of TGFbeta1. However, at high concentrations, estrogen and progesterone (100 nM 17beta-estradiol or 200 nM progesterone) decreased the level of TGFbeta receptor expression. Thus, the progressive rise of steroid levels in vivo might account for the observed changes in TGFbeta1 and TGFbeta 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 for parturition at term.

The Influence of Interleukin (IL)-1β and IL-6 and Tumour Necrosis Factor-α on Prostaglandin Secretion from Porcine Myometrium during the First Third of Pregnancy

“…The different ability of cytokines to release PGs in several days of gestation may arise from diverse expression of receptors for particular cytokines in myometrium during pregnancy. To our knowledge, there are only data showing the expression of receptors for IL-1 and IL-8 in human myometrium at term (Hatthachote and Gillespie 1999). As we demonstrated here, cytokines used individually (at a dose of 1 and/or 10 ng/ml) increased more often the output of PGE 2 compared to PGF 2α from myometrial tissues.…”

Endocrine immune interactions in human parturition

“…With respect to cytokine expression, estrogen in the high concentrations seen in pregnancy can inhibit proinflammatory pathways which include those activated by IL-1β (Polan et al, 1989), IL-6 (Keck et al, 1998, Kikuchi et al, 2000, IL-8 (Rodriguez et al, 2002) and TNF-α (Rogers and Eastell, 2001) as well as inhibiting the activity of natural killer cells (Seaman and Gindhart, 1979). In contrast, the secretion of 'anti-inflammatory interleukins' IL-4 (Kamada et al, 2001), IL-10 (Kanda and Tamaki, 1999) and transforming growth factor (TGF)-β (Hatthachote and Gillespie, 1999) are stimulated by estrogen in these high levels. Notwithstanding these clear anti-inflammatory effects of estrogen, in vivo estradiol can augment the production of pro-inflammatory cytokines by CD4+ T cells (Maret et al, 2003) likely via a direct effect as circulating leukocytes express ER-α (Straub, 2007).…”

The expression of transforming growth factor β in pregnant rat myometrium is hormone and stretch dependent

“…In placental trophoblasts and myometrial smooth muscle cells (SMCs), TGFb has been shown to up-regulate the expression of fibronectin, a marker of preterm labor (Goldenberg et al 1997. TGFbs mRNA and proteins are expressed in the human myometrium during menstrual cycle (Chegini et al 1994) and pregnancy , Kuscu et al 2001, and have been suggested to play a central role regulating excitability and contractility in the human myometrium at term (Hatthachote & Gillespie 1999).…”