The expression of interleukin-6 (IL-6), IL-6 receptor, and gp130-kilodalton glycoprotein in the rat decidua and a decidual cell line: Regulation by 17 beta-estradiol and prolactin

The cytokine interleukin 6 (IL-6), a major mediator of immune and acute pha se responses of the liver, has been implicated in the termination of pregna ncy once expressed in the uterus. This study was undertaken to investigate the expression and regulation of genes encoding IL-6 and IL-6 receptor (IL- GR) in rat decidual tissue. Total RNA obtained from rat decidual tissue on different days of pseudopregnancy was analyzed by RT-PCR using specific pri mers for IL-6, IL-GR, and 130-kDa glycoprotein (gp130). Ribosomal L19 prime rs served as an internal control. IL-GR and gp130 were found to be expresse d in the decidua throughout development, while no messenger RNA (mRNA) for IL-6 was detected. Interestingly, within several hours of culture, decidual explants acquired the ability to express IL-6. The apparent ability of dec idual cells to express IL-6 and its lack of expression in vivo led us to ex amine whether the IL-6 gene is actively inhibited. Primary decidual cells w ere cultured in the presence of estradiol, progesterone, or PRL. Progestero ne showed no effect, whereas estradiol and PRL reduced the level of IL-6 mR NA expression. To examine the mechanism by which these hormones inhibit IL- 6 expression, we used a simian virus 40-transformed decidual cell line (GG- AD), which expresses only estrogen receptor-beta (ER beta). Like primary de cidual cells in culture, GG-AD cells express IL-6, IL-GR, and gp130 mRNA. W hen cultured in the presence of estradiol (0-100 ng/ml), mRNA for IL-6 and its receptor components were down-regulated in a dose-dependent manner. Est radiol also caused a dose-dependent decrease in IL-6 protein secretion into the culture medium. The inhibitory effect of estradiol on IL-6 mRNA expres sion was reversed by the antiestrogen ICI-164,384. Similar inhibition of IL -6 and gp130 mRNA expression was observed with PRL treatment. However, PRL had no effect on IL-GR mRNA levels. PRL inhibition of IL-6 expression was t otally reversed by tyrphostin AG490, a JAK2 inhibitor. In summary, the resu lts of this investigation indicate that IL-6 expression, which is detriment al to the maintenance of pregnancy, is inhibited in the rat decidual tissue . This inhibition is induced by PRL and estradiol, which down-regulate not only IL-6 expression, but also the expression of IL-6 receptor and signalin g proteins. The results also suggest that PRL signaling to the IL-6 gene is mediated through the long form of PRL receptor and involves JAK2 activatio n, whereas that of estradiol can be transduced by estrogen receptor-beta.