Preeclampsia, a common pregnancy disorder associated with an increase in systemic inflammation, is the leading cause of maternal and fetal morbidity and mortality throughout the world. It is associated with shallow extravillous trophoblast invasion of the decidua, leading to uteroplacental blood flow that is inadequate for the developing fetal-placental unit. In preeclamptic women, interleukin-6 (IL-6) levels in plasma, but not placenta, are elevated, prompting evaluation of the decidua as a potential source of this excess, circulating IL-6. The current study found significantly higher immunohistochemical staining for IL-6 in decidual cells from preeclamptic versus preterm, gestational age-matched control placentas. Proinflammatory cytokines associated with the genesis of preeclampsia (i.e., tumor necrosis factor-␣ and interleukin-1␤) enhanced IL-6 mRNA levels and increased secreted IL-6 levels in first trimester leukocytefree decidual cell incubations, as measured by real time quantitative RT-PCR , ELISA , and Western blotting. Therefore , decidual cell-derived IL-6 may contribute to excess circulating IL-6 levels that can promote both endothelial cell dysfunction (and subsequent vascular dysfunction) and the pathogenesis of preeclampsia whereas locally elevated IL-6 levels may contribute to an excess of decidual macrophages implicated in shallow extravillous trophoblast invasion of the decidua. Maternal-fetal interactions create a mild systemic inflammatory state exemplified by activation of both vascular endothelium and leukocytes that is most apparent in the third trimester of uncomplicated human pregnancies.

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Preeclampsia is characterized by an exaggerated systemic inflammatory state as well as shallow placentation. In the decidual implantation site , preeclampsia is accompanied by an excessive number of both macrophages and dendritic cells as well as their recruiting chemokines, which have been implicated in the impairment of endovascular trophoblast invasion. Granulocyte-macrophage colony-stimulating factor is known to regulate the differentiation of both macrophages and dendritic cells, prompting both in vivo and in vitro evaluation of granulocyte-macrophage colony-stimulating factor expression in human decidua as well as in a mouse model of preeclampsia. This study revealed increased granulocyte-macrophage colony-stimulating factor expression levels in preeclamptic decidua. Moreover, both tumor necrosis factor-␣ and interleukin-1 ␤, cytokines that are implicated in the genesis of preeclampsia, markedly up-regulated granulocyte-macrophage colony-stimulating factor production in cultured first-trimester human decidual cells. The conditioned media of these cultures promoted the differentiation of both macrophages and dendritic cells from a monocyte precursor. Evaluation of a murine model of preeclampsia revealed that the decidua of affected animals displayed higher levels of immunoreactive granulocyte-macrophage colony-stimulating factor as well as increased numbers of both macrophages and dendritic cells when compared to control animals. Because granulocyte-macrophage colony-stimulating factor is a potent inducer of differentiation and activation of both macrophages and dendritic cells , these findings suggest that this factor plays a crucial role in the pathogenesis of preeclampsia. (Am J

Human extravillous trophoblast (EVT) invades the decidua via integrin receptors and subsequently degrades extracellular matrix proteins. In preeclampsia (PE), shallow EVT invasion elicits incomplete spiral artery remodeling, causing reduced uteroplacental blood flow. Previous studies show that preeclamptic decidual cells, but not interstitial EVTs, display higher levels of extracellular matrix-degrading matrix metalloproteinase (MMP)-9, but not MMP-2. Herein, we extend our previous PE-related assessment of MMP-2 and MMP-9 to include MMP-1, which preferentially degrades fibrillar collagens, and MMP-3, which can initiate a local proteolytic cascade. In human first-trimester decidual cells incubated with estradiol, tumor necrosis factor-α (TNF-α) significantly enhanced MMP-1, MMP-3, and MMP-9 mRNA and protein levels and activity measured by real-time quantitative RT-PCR, ELISA, immunoblotting, and zymography, respectively. In contrast, interferon γ (IFN-γ) reversed these effects and medroxyprogesterone acetate elicited further reversal. Immunoblotting revealed that p38 mitogen-activated protein kinase signaling mediated TNF-α enhancement of MMP-1, MMP-3, and MMP-9, whereas IFN-γ inhibited p38 mitogen-activated protein kinase phosphorylation. Unlike highly regulated MMP-1, MMP-3, and MMP-9, MMP-2 mRNA and protein expression was constitutive in decidual cells. Because inflammation underlies PE-associated shallow EVT invasion, these results suggest that excess macrophage-derived TNF-α augments expression of MMP-1, MMP-3, and MMP-9 in decidual cells to interfere with normal stepwise EVT invasion of the decidua. In contrast, decidual natural killer cell-derived IFN-γ reverses such TNF-α-induced MMPs to protect against PE.

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Introduction Little is known about the relationship between Behçet’s disease (BD) and female sexual dysfunction (FSD). Aims The aims were to evaluate the prevalence of FSD in premenopausal BD patients and to compare hormonal and psychiatric conditions to healthy subjects. Methods A total of 71 married women with BD and 63 healthy married women between 18 and 44 years old were enrolled into the study. After evaluating detailed history and physical examination, serum steroid hormone levels were measured. Presence of genital ulcerations in physical examination and any medical treatment were recorded in patients. All subjects were asked to complete the Female Sexual Function Index (FSFI) for sexual status and Beck Depression Inventory (BDI) for psychiatric assessment. Main Outcomes Measures FSFI and BDI scores and serum sex steroid hormone levels were measured in women with BD and healthy controls. Results The mean BDI score of patients was significantly greater than that for controls (P = 0.001), and there was a statistically significant difference between BDI scores (Pearson χ2 = 19.109, P = 0.001). FSD was found in 34 patients with BD (47.9%) and in 11 controls (17.5%). A statistically significant difference was found between the two groups (Pearson χ2 = 13.855, P = 0.001). While the most common sexual problem in the patients with BD was diminished arousal (n = 49, 69.0%), diminished desire was found in 32 patients (45.1%) and lubrication problems in 36 patients (50.7%). There was a statistically significant negative correlation between BDI and FSFI score in BD patients. On the contrary, there was no relationship between FSFI and presence of genital ulcerations. Conclusion FSD is more common in BD patients than in healthy subjects. We conclude that depressive mood according to the BDI scale correlates with the sexual status of BD patients, and this may be because of the depressive effect of BD as a chronic disease.

The human endometrium is a dynamic tissue that undergoes cyclic changes under the influence of steroid hormones as well as numerous local paracrine and autocrine factors. Heat shock 70 kDa protein (HSPA5; also known as GRP78/BiP), a molecular chaperone within the endoplasmic reticulum, plays crucial roles in normal cellular processes as well as in stress conditions, in which it is a central regulator for the unfolded protein response (UPR). We hypothesized that HSPA5 expression level is variable throughout the menstrual cycle in human endometrium and that estrogen signaling cross-talks with UPR signaling by interacting with HSPA5. HSPA5 expression throughout the menstrual cycle was evaluated in vivo in normal human endometrium. Using in vitro techniques, we then assessed the bidirectional regulation of HSPA5 and estrogen signaling in human endometrial glandular (Ishikawa) and stromal cells (ESC). HSPA5 immunoreactivity in endometrial glandular and stromal cells was cycle-dependent, and was significantly higher in phases of the menstrual cycle when estradiol (E(2)) levels are known to be the lowest compared with the rest of the cycle (P < 0.001). E(2) did not affect HSPA5 expression after 8-24 h incubation in Ishikawa cells and ESC in vitro. However, tunicamycin-induced HSPA5 expression was significantly lowered in these cells when pretreated with E(2) (P < 0.01 and P < 0.05, respectively). On the other hand, tunicamycin decreased E(2) up-regulated alkaline phosphatase activity (P < 0.001). In conclusion, there is cycle-dependent HSPA5 expression with a possible inverse correlation between HSPA5 expression and E(2) levels in human endometrium. We suggest that estrogen signaling cross-talks with the UPR cascade by interacting with HSPA5, as supported by our in vitro findings.

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