Inhibition of 15-hydroxy prostaglandin dchydrogenasc expression and activity by cytokines in human placental trophoblasts

Keelan, Jeffrey; Mesnage, Stéphane; Goodwin, V; Mitchell, M. D.

doi:10.1016/s1071-5576(97)86115-1

Cited by 6 publications

(7 citation statements)

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“…These results have been substantiated using chorion explant cultures [26], and reduced PGDH activity was correlated with reduced levels of PGDH mRNA in chorion explant and chorion trophoblast cultures, but not in villous trophoblast cultures from patients at labor. This observation has been substantiated recently by others [14]. PGDH activity in placenta and chorion trophoblast cells was diminished significantly, in a dosedependent fashion by both cortisol and the synthetic glucocorticoid, dexamethasone [22].…”

Section: Prostaglandin Dehydrogenasesupporting

confidence: 60%

“…Chorion collected from the region of the internal os overlying the cervix from women at term, elective Caesarean section in the absence of labor had higher PGDH activity in that region than in chorion collected from an area adjacent to the placenta, or intermediate. Studies by Keelan and colleagues have shown that cytokines such as IL-1b decrease PGDH mRNA levels, and this is correlated with loss of PGDH activity [14]. Med.…”

Section: Prostaglandin Dehydrogenasementioning

confidence: 99%

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Prostaglandin dehydrogenase and the initiation of labor

Challis¹,

Patel²,

Pomini³

1999

Journal of Perinatal Medicine

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In summary, these studies have suggested that prostaglandin dehydrogenase may have a central role to play in the mechanisms which determine biologically active prostaglandin concentrations within human fetal membranes and placenta at the time of labor, at term or preterm. Moreover, our studies indicate that the regulation of PGDH may by multifactorial (figure 3). In certain regions of the membranes, we suggest that PGDH expression may be influenced by levels of anti-inflammatory and pro-inflammatory cytokines. In other regions of the membranes, we suggest that PGDH may be regulated at a transcriptional level by competing activities of progesterone and cortisol. The action of progesterone could be effected through systemically-derived steroid, or by locally synthesized steroid, acting in a paracrine and/or autocrine fashion. The effects of cortisol in placenta must be due to glucocorticoid derived from the maternal or fetal compartment, since the placenta lacks the hydroxylases required for endogenous cortisol production. However, metabolism of cortisol by 11 beta-HSD-2 reduces the potency of this glucocorticoid in placental tissue. In chorion however, cortisol may be formed locally, from cortisone, in addition to its being derived from the maternal circulation and/or from the amniotic fluid. Our current studies do not allow us to delineate whether the effects of progesterone and cortisol on PGDH are exerted through the glucocorticoid receptor (GR) or progesterone receptor (PR) or both. It is possible that through pregnancy, PGDH activity is maintained by progesterone acting either through low levels of PR in membranes, or, more likely, acting through GR. At term, elevated levels of cortisol compete with and displace progesterone from GR, resulting in inhibition of PGDH transcription and activity. In this way, local withdrawal of progesterone action would be effected within human intrauterine tissues, without requiring changes in systemic, circulating progesterone concentrations. Since glucocorticoids appear also to increase expression of prostaglandin synthesizing enzymes within the amnion and chorion, directly by upregulating PGHS-2, or indirectly through the intermediary action of a paracrine effector such as CRH, their role in coordinating processes of parturition remains central. Further understanding of the regulation of PGDH may be of therapeutic importance. For example, it is possible that PGDH activity in lower segment chorion may be reduced in those patients with premature cervical softening, or may be particularly high in those patients with an unfavorable cervix, presenting with a low Bishop score and poor progression at the time of labor. If the enzyme in this region crucially determines the passage and availability of biologically active prostaglandins from amnion and chorion to underlying cervix, then pharmacologic manipulation of PGDH activity may effectively regulate PG transfer in these clinical conditions. Glucocorticoids appear to have a central role in promoting production of agents that are u...

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Section: Prostaglandin Dehydrogenasesupporting

confidence: 60%

Section: Prostaglandin Dehydrogenasementioning

confidence: 99%

Prostaglandin dehydrogenase and the initiation of labor

Challis¹,

Patel²,

Pomini³

1999

Journal of Perinatal Medicine

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“…Keelan et al (22) reported recently that PGDH mRNA levels were reduced to 25% of the control level in trophoblast cells treated with IL-1␤, a greater degree of inhibition, but a similar pattern as in the present study. Despite this finding, our results show that the output of both PGE 2 and PGFM from villous trophoblasts rose during exposure to IL-1␤.…”

Section: Discussionsupporting

confidence: 90%

“…These cytokines influence not only the immune response, but can also activate the PG biosynthetic pathway in several feto-maternal tissues (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Few studies, however, have examined their effects on key PG-metabolizing enzymes (22). When PGs are produced at the feto-maternal (chorio-decidual) interface, labor can be induced.…”

mentioning

confidence: 99%

Interleukin-10 Modifies the Effects of Interleukin-1β and Tumor Necrosis Factor-α on the Activity and Expression of Prostaglandin H Synthase-2 and the NAD⁺-Dependent 15-Hydroxyprostaglandin Dehydrogenase in Cultured Term Human Villous Trophoblast and Chorion Trophoblast Cells¹

Pomini

Caruso

Challis

1999

The Journal of Clinical Endocrinology & Metabolism

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The concentrations of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta), two inflammatory cytokines in amniotic fluid, have been shown to rise during chorioamnionitis. This is probably related to activation of the immune system in order to intensify the inflammatory process and to protect the maternal and fetal organism from infectious agents. These cytokines activate the PG biosynthetic pathway in several tissues, but few studies have examined effects on PG-metabolizing enzymes. When PGs are produced by increased synthesis and/or decreased metabolism at the chorio-decidual interface, labor can be induced. Interleukin-10 (IL-10) is known to act as an antiinflammatory cytokine. The goals of this study were to evaluate the interaction of IL-10 with IL-1beta and TNFalpha on PG synthesis and to determine the effects of IL-10, IL-1beta, and TNFalpha on PG metabolism using purified cultures of villous trophoblast and chorion trophoblast cells prepared from placentas of patients at term. Cells were treated with IL-1beta and TNFalpha with or without IL-10 for various times up to 24 h. Levels of messenger ribonucleic acid (mRNA) encoding PGH synthase-2 (PGHS-2) and NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) were quantified by Northern blotting, and PGE2 and 13,14-dihydro-15-keto-PGF2alpha (PGFM) output in the medium was measured by RIA. IL-1beta increased PGHS-2 mRNA and PGE2 output from villous and chorion trophoblasts and decreased PGDH mRNA in villous trophoblasts (all P < 0.05). These effects were reversed by IL-10. We found no change in PGHS-2 mRNA or PGE2 output in either trophoblast type treated with TNFalpha, but TNFalpha reduced PGDH mRNA in villous trophoblast, and this effect was reversed by IL-10 (both P < 0.05). We conclude that proinflammatory cytokines can influence PG output through effects on PG synthesis and metabolism and that these effects may be opposed by an antiinflammatory cytokine. These interactions may be important in the progression of preterm labor with underlying infection and in term labor in regions of the uterus where cytokine production is increased.

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“…DEX escapes extensive metabolism in chorion and placenta, and it inhibits PGDH in both tissues. In addition, it is possible that other factors, including cytokines, are involved in the regulation of PGDH in intrauterine tissues, particularly in the setting of infection (48).…”

Section: Discussionmentioning

confidence: 99%

Local Modulation by 11 -Hydroxysteroid Dehydrogenase of Glucocorticoid Effects on the Activity of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion and Placental Trophoblast Cells

Patel¹

1999

Journal of Clinical Endocrinology & Metabolism

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NAD+-dependent 15-hydroxy-PG dehydrogenase (PGDH) is the major enzyme involved in the initial inactivation of PGs, and its activity is reduced by glucocorticoids, cortisol (F), and dexamethasone (DEX). In turn, glucocorticoid regulation of PGDH activity in placenta and chorion could be regulated indirectly by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity. In the placenta, 11beta-HSD2 is the dominant isoform, acting as a dehydrogenase [F to cortisone (E)]; and in chorion, 11beta-HSD1 predominates as a reductase (E to F). The present study was designed to determine whether glucocorticoid regulation of PGDH activity in placenta and chorion could be regulated indirectly by 11beta-HSD activity. We obtained Percoll-purified human placental and chorion trophoblast cells from uncomplicated term pregnancies, cultured them for 72 h, then treated the cells with cortisol (100 nmol/L), cortisone (1 micromol/L), or DEX (100 nmol/L), in the presence or absence of carbenoxolone (CBX, 800 nmol/L), an 11beta-HSD inhibitor, for 24 h. Activity of PGDH was assessed by incubation (4 h) with PGF2alpha (282 nmol/L) and measurement of conversion to 13,14-dihydro-15-keto PGF2alpha. CBX alone had no effect on PGDH activity in either placenta or chorion trophoblast cells. In chorion, E significantly inhibited PGDH activity, and this effect was reversed by addition of CBX. F and DEX significantly inhibited PGDH, and this effect was unaltered by coadministration of CBX. In contrast, in placenta, there was no effect of E, or of E with CBX, on PGDH activity. However, F and DEX inhibited PGDH, and the effect of F (but not DEX) was greater in the presence of CBX. In conclusion, we suggest that effects of E and F on PGDH are modified by the tissue-specific expression of 11beta-HSD isoforms.

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Inhibition of 15-hydroxy prostaglandin dchydrogenasc expression and activity by cytokines in human placental trophoblasts

Cited by 6 publications

References 0 publications

Prostaglandin dehydrogenase and the initiation of labor

Prostaglandin dehydrogenase and the initiation of labor

Interleukin-10 Modifies the Effects of Interleukin-1β and Tumor Necrosis Factor-α on the Activity and Expression of Prostaglandin H Synthase-2 and the NAD⁺-Dependent 15-Hydroxyprostaglandin Dehydrogenase in Cultured Term Human Villous Trophoblast and Chorion Trophoblast Cells¹

Local Modulation by 11 -Hydroxysteroid Dehydrogenase of Glucocorticoid Effects on the Activity of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion and Placental Trophoblast Cells

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Inhibition of 15-hydroxy prostaglandin dchydrogenasc expression and activity by cytokines in human placental trophoblasts

Cited by 6 publications

References 0 publications

Prostaglandin dehydrogenase and the initiation of labor

Prostaglandin dehydrogenase and the initiation of labor

Interleukin-10 Modifies the Effects of Interleukin-1β and Tumor Necrosis Factor-α on the Activity and Expression of Prostaglandin H Synthase-2 and the NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase in Cultured Term Human Villous Trophoblast and Chorion Trophoblast Cells1

Local Modulation by 11 -Hydroxysteroid Dehydrogenase of Glucocorticoid Effects on the Activity of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion and Placental Trophoblast Cells

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Interleukin-10 Modifies the Effects of Interleukin-1β and Tumor Necrosis Factor-α on the Activity and Expression of Prostaglandin H Synthase-2 and the NAD⁺-Dependent 15-Hydroxyprostaglandin Dehydrogenase in Cultured Term Human Villous Trophoblast and Chorion Trophoblast Cells¹