Orthodontic tensile strain induces angiogenesis via type IV collagen degradation by matrix metalloproteinase-12.

BACKGROUND AND OBJECTIVE: During orthodontic tooth movement (OTM), periodontal ligament (PDL) is remodeled dynamically, which requires sufficient blood supply for the regeneration of PDL. However, little is known about the remodeling of blood vessels during OTM. In this study, we hypothesized that the orthodontic tensile strain upregulates matrix metalloproteinase-12 (MMP-12) expression in the tension zone and induces angiogenesis via degradation of type IV collagen (Col-IV) in vascular endothelial basement membrane during the early stage of OTM. MATERIAL AND METHODS: Temporal and spatial MMP-12 expression in the tension zone of PDL, during the early stage of OTM, were examined by immunohistochemistry in rats. Continuous tensile strain was applied to cultured human immortalized PDL cell lines (HPL cells) and MMP-12 expression was examined in vitro. Colocalization of MMP-12 and Col-IV in vivo were examined by immunohistochemistry. To investigate whether MMP-12 produced by HPL cells could degrade Col-IV, recombinant Col-IV was incubated in the culture supernatants of HPL cells. Intact Col-IV in vitro was also examined by western blot analysis. Finally, the changes in blood vessels in the PDL were examined by micro-computed tomography analysis with perfused contrast agents and by conventional histological analysis. RESULTS: Orthodontic tensile strain induced MMP-12 expression in PDL cells in vivo and in vitro. Immunohistochemistry revealed that MMP-12-positive cells were observed adjacent to the Col-IV-positive tubular area in the tension zone of PDL. MMP-12 in culture supernatant of HPL cells degraded recombinant Col-IV, and specific MMP-12 inhibitor blocked the Col-IV degradation. Micro-computed tomography analysis and conventional histological analysis demonstrated that the areas of blood vessels were increased in the tension zone of the PDL after OTM. CONCLUSION: We discovered that the orthodontic tensile strain upregulates MMP-12 expression in the tension zone of PDL and induces angiogenesis via degradation of Col-IV in the vascular endothelial basement membrane.

Intralesional steroid injection to prevent stricture after endoscopic submucosal dissection for esophageal cancer: a controlled prospective study.

BACKGROUND AND STUDY AIMS: The frequency of stricture after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma with a mucosal defect involving more than three-quarters of the circumference is 70% - 90%. Stricture decreases quality of life and requires multiple endoscopic balloon dilation (EBD) sessions. We investigated the efficacy and safety of a single session of intralesional steroid injections to prevent post-ESD stricture. PATIENTS AND METHODS: We conducted a prospective study on 30 patients with esophageal squamous cell carcinoma treated by ESD, who had a more than three-quarter but less than whole circumferential defect. A single session of intralesional steroid injections was undertaken immediately after ESD. Esophagogastroduodenoscopy was performed whenever patients reported dysphagia and 2 months after ESD in patients without dysphagia. Results were compared with a historical control group of 29 patients who underwent ESD without intralesional steroid injection. The primary endpoint was the post-ESD stricture rate. Secondary endpoints were the number of EBD sessions and the complication rate. RESULTS: Compared with the historical control group, the study group had a significantly lower stricture rate (10%, 3/30 patients vs. 66%, 19/29 patients; P < 0.0001) and a lower number of EBD sessions (median 0, range 0 - 2 vs. median 2, range 0 - 15; P < 0.0001). The study group had a complication rate of 7 % (2 /30 patients), comprising a submucosal tear in one patient and bleeding in another, which were not a direct result of EBD. CONCLUSIONS: A single session of intralesional steroid injections showed promising results for the prevention of stricture after ESD for esophageal cancer.

Effects of local osteoprotegerin gene transfection on orthodontic root resorption during retention: an in vivo micro-CT analysis.

OBJECTIVES: External root resorption (ERR) is a serious complication of orthodontic treatment. Aim of this study was to evaluate the effects of local osteoprotegerin (OPG) gene transfection on ERR during retention. MATERIAL AND METHODS: Eighteen 6-week-old male Wistar rats were divided into three groups. All the rats were subjected to 2 weeks of orthodontic tooth movement followed by a 2-week retention period. During retention, the three groups of rats received local OPG gene transfection (OPG transfection group, n=6), mock vector transfection (mock group, n=6), or no injections (control group, n=6). ERR of all three groups was evaluated with in vivo micro-CT analysis at three different time points: baseline, the last day of orthodontic tooth movement, and the last day of retention. RESULTS: In the OPG transfection group, there was no significant difference between ERR at the baseline and ERR on the last day of retention. By the last day of retention, the repair ratio of ERR in the OPG transfection group was statistically higher in relation to the repair ratio of the other groups (p<0.001). CONCLUSION: The results indicated that local OPG gene transfection significantly enhanced the repair of ERR during retention. Local OPG gene transfection might therefore be a useful tool for ERR repair during retention.

Prenatal diagnosis of fetal left pulmonary artery sling.

Left pulmonary artery (LPA) sling is a very rare anomaly in which the LPA arises distally, far from the right pulmonary artery on the right side of the distal trachea, turns sharply leftwards around the trachea and courses to the left lung hilum through the space between the trachea and esophagus. LPA sling is often associated with distal tracheal narrowing, due to either intrinsic stenosis or secondary compression by the anomaly itself. To our knowledge, prenatal diagnosis of LPA sling has not been reported so far. We report a case in which LPA sling was diagnosed during fetal ultrasound examination.

Clinical features and outcomes of delayed perforation after endoscopic submucosal dissection for early gastric cancer.

Perforation is a major complication of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). However, there have been no reports on delayed perforation after ESD for EGC. We aimed to elucidate the incidence and outcomes of delayed perforation after ESD. Clinical courses in 1159 consecutive patients with 1329 EGCs who underwent ESD were investigated. Delayed perforation occurred in six patients (0.45 %). All these patients had complete en bloc resection without intraoperative perforation during ESD. Five of six perforations were located in the upper third of the stomach, while one lesion was found in the middle third. Symptoms of peritoneal irritation with rebound tenderness presented within 24 h after ESD in all cases. One patient did not require surgery because the symptoms were localized, and recovered with conservative antibiotic therapy by nasogastric tube placement. The remaining five patients required emergency surgery. There was no mortality in this case series.

Altered activity of lysophospholipase D, which produces bioactive lysophosphatidic acid and choline, in serum from women with pathological pregnancy.

Altered lipid metabolism is associated with human abnormal pregnancy, such as pre-eclampsia and preterm labor, and potentially leads to fetus loss. A causative factor for the onset and progress of the systemic multifactorial syndromes associated with the pathological pregnancy is oxidized low-density lipoprotein, an active identity of which was postulated to be lysophosphatidic acid (LPA). We previously found that LPA is produced extracellularly by plasma lysophospholipase D (lysoPLD) activity of autotaxin, a tumor cell motility-stimulating protein. In this study, a convenient assay based on the choline released from endogenous substrate or exogenous lysophosphatidylcholine (LPC) was used for comparison of serum lysoPLD activity among patients with normal and abnormal pregnancy. The serum choline-producing activity was found to be mainly due to autotaxin, and dependent on its dilution rate. There was some association between low dilution dependency of serum lysoPLD activity toward an exogenous LPC and high lysoPLD activity toward endogenous substrates in cases of patients with preterm labor and pre-eclampsia. However, there was no difference in the serum level of LPC between women with normal pregnancy and those with pathological pregnancy. These results indicate that production of bioactive LPA by lysoPLD activity is elevated by an unknown mechanism that may be related to increased availability of endogenous substrates LPC, but not its concentration in human serum. If the level of LPA in blood circulation is elevated in the pathological pregnancies in vivo, it may play a role in induction and/or progression of systemic vascular dysfunction seen patients with preterm labor or pre-eclampsia.

Clodronate inhibits PGE(2) production in compressed periodontal ligament cells.

Periodontal ligament (PDL) cells play an essential role in orthodontic tooth movement. We recently reported that clodronate, a non-N-containing bisphosphonate, strongly inhibited tooth movement in rats, and thus could be a useful adjunct for orthodontic treatment. However, it is not clear how clodronate affects the responses of PDL cells to orthodontic force. In this study, we hypothesized that clodronate prevents the mechanical stress-induced production of prostaglandin E(2) (PGE(2)), interleukin-1beta (IL-1beta), and nitric oxide (NO) in human PDL cells. A compressive stimulus caused a striking increase in PGE(2) production, while the responses of IL-1beta and NO were less marked. Clodronate concentration-dependently inhibited the stress-induced production of PGE(2). Clodronate also strongly inhibited stress-induced gene expression for COX-2 and RANKL. These results suggest that the inhibitory effects of clodronate on tooth movement and osteoclasts may be due, at least in part, to the inhibition of COX-2-dependent PGE(2) production and RANKL expression in PDL cells.

Cyclical tensile force on periodontal ligament cells inhibits osteoclastogenesis through OPG induction.

The periodontal ligament (PDL) maintains homeostasis of periodontal tissue under mechanical tensile-loading caused by mastication. Occlusal load inhibits atrophic alveolar bone resorption. Previously, we discovered that continuous compressive force on PDL cells induced osteoclastogenesis-supporting activity, with up-regulation of RANKL. We hypothesized that, unlike compression, cyclical tensile force up-regulates OPG expression in PDL cells via TGF-beta up-regulation, and does not induce osteoclastogenesis-supporting activity. PDL cells were mechanically stimulated by cyclical tensile force in vitro. The conditioned media of PDL cells that had been subjected to cyclical tensile force inhibited osteoclastogenesis. Cyclical tensile force up-regulated not only RANKL mRNA expression, but also OPG mRNA expression in PDL cells. Tensile force up-regulated TGF-beta expression in PDL cells as well. Administration of neutralizing antibodies to TGF-beta inhibited OPG up-regulation under cyclical tensile-force stimulation in a dose-dependent manner. Additionally, the osteoclastogenesis-inhibitory effect of the conditioned media of PDL cells under cyclical tensile force was partially rescued by the administration of TGF-beta neutralizing antibodies. In conclusion, tensile force inhibited the osteoclastogenesis-supporting activity of PDL cells by inducing the up-regulation of OPG via TGF-beta stimulation.

Insight into the active site of Streptomyces cystathionine gamma-lyase based on the results of studies on its substrate specificity.

The results of studies on the substrate specificities of elimination and replacement reactions allowed insight into the active and regulatory sites of Streptomyces phaeochromogenes cystathionine gamma-lyase (L-cystathionine cysteine-lyase (deaminating), EC 4.4.1.1). The enzyme has an active site and a regulatory site. The active site consists of two subsites; one recognizes the L-forms of amino acids (L-homoserine and L-moieties of cystathionine isomers) and the other shows affinity for thiol compounds with a carboxyl group. The regulatory site is specific for L-cysteine and has no affinity for ordinary thiol compounds, such as 3-mercaptopropionate and thioglycolate.

Nrf2 activation attenuates both orthodontic tooth movement and relapse.

During orthodontic tooth movement, osteoclasts resorb the alveolar bone at the compress side of periodontium. Reactive oxygen species (ROS) works as intracellular signaling molecules of RANKL during osteoclastogenesis, although ROS has cytotoxicity against cells such as lipid oxidation. To deal with oxidative stress, cells have a defense system that is scavenging ROS by augmented antioxidative stress enzymes via transcriptional regulation with nuclear factor E2-related factor 2 (Nrf2). Previously, we reported that augmented antioxidative stress enzymes by Nrf2-gene transfer inhibited bone destruction. In the present study, we examined the effects of Nrf2 activation on osteoclastogenesis and, thereby, orthodontic tooth movement and orthodontic relapse. Mouse macrophage cell line RAW264.7 cells were used as osteoclast progenitor cells and stimulated with recombinant RANKL (100 ng/mL) with or without Nrf2 activator sulforaphane (SFN) and epigallocatechin gallate (EGCG) or ROS scavenger catechin. Osteoclastogenesis, resorption activity, and osteoclast marker gene expression were examined. Intracellular ROS was analyzed by flow cytometry. Maxillary first molars of C57BL6 male mice were moved palatally with 0.012-inch NiTi wire (100-mN force); SFN or EGCG was injected into the palatal gingiva once a week; and phosphate buffered saline was injected on the contralateral side. Tooth movement was monitored using a stone model with precise impression, and the amount of the tooth movement was compared among groups. SFN and EGCG significantly, but catechin weakly, inhibited RANKL-mediated osteoclastogenesis in vitro. Western blot analysis revealed that SFN and EGCG augmented the nuclear translocation of Nrf2 and the expression of anti-oxidative stress enzymes such as HO-1, although catechin did not. SFN and EGCG significantly, but catechin weakly, attenuated the intracellular ROS. Finally, animal experiment revealed that both SFN and EGCG successfully inhibited the orthodontic tooth movement. Additionally, SFN inhibited the relapse. These results suggest that Nrf2 activation could be therapeutic target for the anchorage enforcement in orthodontic treatment and pharmacologic retention against relapse.

Structural basis of pathogen recognition by an integrated HMA domain in a plant NLR immune receptor.

Plants have evolved intracellular immune receptors to detect pathogen proteins known as effectors. How these immune receptors detect effectors remains poorly understood. Here we describe the structural basis for direct recognition of AVR-Pik, an effector from the rice blast pathogen, by the rice intracellular NLR immune receptor Pik. AVR-PikD binds a dimer of the Pikp-1 HMA integrated domain with nanomolar affinity. The crystal structure of the Pikp-HMA/AVR-PikD complex enabled design of mutations to alter protein interaction in yeast and in vitro, and perturb effector-mediated response both in a rice cultivar containing Pikp and upon expression of AVR-PikD and Pikp in the model plant Nicotiana benthamiana. These data reveal the molecular details of a recognition event, mediated by a novel integrated domain in an NLR, which initiates a plant immune response and resistance to rice blast disease. Such studies underpin novel opportunities for engineering disease resistance to plant pathogens in staple food crops.

Increased type 2 cytokine expression by both CD4+ CD45RO+ T cells and CD8+ CD45RO+ T cells in blood circulation is associated with high serum IgE but not with atopic dermatitis.

Type 2 cytokines, such as interleukin-4 (IL-4) and IL-13, are associated with immunoglobulin E (IgE) production. This association has also been observed in CD8+ T cells from patients infected with leprosy and human immunodeficiency virus (HIV). Using intracellular cytokine staining and flow cytometry, the cytokine profile [IL-2, IL-4, IL-10, IL-13, and interferon (IFN)-gamma] of both CD4+ and CD8+ memory/effector T cells circulating in atopic dermatitis (AD) patients was investigated at the single cell level. The levels of type 2 cytokines in CD4+ T cells or CD8+ T cells in AD patients with high levels of serum IgE (AD-H), low levels of serum IgE (AD-L), and healthy controls were compared. Increased production of IL-4 and IL-13 in both CD4+ CD45RO+ T cells and CD8+ CD45RO+ T cells after 4 h in vitro stimulation with phorbol 12-myristate 13-acetate and ionomycin, was more prominent in AD-H patients than in AD-L patients or healthy controls, whereas IFN-gamma-producing CD4+ CD45RO+ T cells and CD8+ CD45RO+ T cells were relatively diminished in AD-H patients. CD4+ T cells and CD8 + T cells from AD-H patients, cultured for 48 h with phorbol 12-myristate 13-acetate and ionomycin, released larger amounts of IL-4 and IL-13 but smaller amounts of IFN-gamma than both types of cells from AD-L patients or healthy controls. In addition, when stimulated with immobilized anti-CD3 monoclonal antibody (MoAb) and anti-CD28 MoAb, CD4+ CD45RO+ T cells and CD8+ CD45RO+ T cells from AD-H patients contained more IL-4-producing cells but fewer IFN-gamma-producing cells compared with healthy controls. Finally, spontaneous mRNA expression of IL-4 in blood CD8+ CD45RO+ T cells isolated from AD-H patients was increased, as determined by reverse transcriptase-polymerase chain reaction. Therefore, in AD patients with high IgE levels, type 2 cytokine (IL-4 and IL-13) expression is associated with IgE production, in both CD4+ CD45RO+ T cell and CD8+ CD45RO+ T cell subsets.

Induction of thioredoxin, a redox-active protein, by ovarian steroid hormones during growth and differentiation of endometrial stromal cells in vitro.

Human thioredoxin (hTrx) is a cellular redox-active protein that catalyzes dithiol/disulfide exchange reactions, thus controlling multiple biological functions, including cell growth-promoting activity. Here we show that the expression of hTrx protein and messenger RNA was up-regulated by incubation with 17beta-estradiol (E2) in primary culture of stromal cells isolated from human endometrium. Maximal enhancement of hTrx protein and messenger RNA was observed after 6-12 h of incubation with 10-100 nM E2, and the enhancing effect was suppressed by tamoxifen, an estrogen antagonist. Release of hTrx into the culture medium was markedly augmented after 5-day exposure of E2 plus progesterone (P) accompanied by in vitro differentiation of endometrial stromal cells (decidualization). Immunocytochemical studies showed that hTrx was localized in the nucleus, nucleolus, and cytosol in the stromal cells. Strongly enhanced immunoreactivity for hTrx was observed in the E2-treated cells, whereas there was no apparent difference in the pattern of subcellular localization among the untreated and E2- and/or P-treated cells. Although 1-50 microg/ml recombinant hTrx alone did not promote endometrial stromal cell growth, epidermal growth factor-dependent mitogenesis was additively enhanced by hTrx. Our results indicate that hTrx modulates endometrial cell growth, acting as a comitogenic factor for epidermal growth factor, which is known to be a mediator of estrogen action. It is also suggested that hTrx is deeply involved in the hormonal control of the endometrium by E2 and P, playing a regulatory role in endometrial cell growth and differentiation.

A new monoclonal antibody (POG-1) detects a differentiation antigen of porcine granulosa and thecal cells and indicates heterogeneity of thecal-stromal cells.

To identify the differentiation antigen of ovarian cells, we raised a murine monoclonal antibody (POG-1 antibody) reactive to porcine granulosa and thecal cells in the ovary. Immunofluorescence staining showed that expression of the POG-1 antigen on granulosa and theca interna cells increased gradually in accordance with follicular development. The thecal cells just outside the basal lamina surrounding the follicles did not express the antigen, whereas some stromal cells around the theca externa layer in the large follicles did express it. These expression profiles indicated the heterogeneity of thecal-stromal cells and that the POG-1 antigen was a differentiation-related antigen of granulosa and thecal cells. Luteal cells also expressed the antigen. In organs other than the ovary, some endocrine and exocrine cells, such as Leydig cells and secretory cells of the breast, expressed the antigen. The POG-1 antigen was purified from granulosa cells by immunoaffinity chromatography. Polyacrylamide gel electrophoresis profiles showed that the antigen consisted of two specific proteins; the major one had a molecular mass of 77, and the other had a molecular mass of 81 kilodaltons. Analysis of the purified POG-1 antigen may contribute to understanding the differentiation mechanism of granulosa and thecal cells.

Progesterone enhances macrophage colony-stimulating factor production in human endometrial stromal cells in vitro.

Increasing evidence suggests that macrophage colony-stimulating factor (M-CSF) is produced in the uterine endometrium and that it plays an important role in the reproductive process. In the present study, using an in vitro decidualization model and human endometrium, we investigated M-CSF messenger RNA (mRNA) expression in human endometrial stromal cells (ESC) by Northern blotting and in situ hybridization. The secreted M-CSF in the culture medium of ESC was measured by enzyme-linked immunosorbent assay. ESC were cultured in the presence of progesterone (P) or estrogen. After a 9-day culture with P, when in vitro decidualization was confirmed by the production of PRL, M-CSF mRNA and protein levels were 3.1 +/- 0.5- and 3.2 +/- 0.8-fold (mean +/- SEM) higher, respectively, than those in cultures without P (P < 0.01). The P-induced increase was dose dependent. On the other hand, estrogen did not increase M-CSF mRNA expression. M-CSF mRNA expression in the first trimester deciduae that expressed PRL mRNA was higher than that in the endometria. By in situ hybridization, ESC as well as epithelial cells were shown to express M-CSF both in vitro and in vivo. These findings indicate that human ESC (decidua cells) express M-CSF mRNA and suggest that they secrete M-CSF in a P-dependent manner during the process of decidualization.

Induction of tissue inhibitor of metalloproteinase 3 gene expression during in vitro decidualization of human endometrial stromal cells.

Endometrial stromal differentiation (decidualization) is essential for implantation of the developing blastocyst. To investigate the process of progesterone (P)-induced decidualization of human endometrial stromal cells (ESC), a complementary DNA library enriched with P-induced genes was constructed from cultured human ESC by subtractive hybridization and the polymerase chain reaction. One of the isolated clones was the complementary DNA for the tissue inhibitor of metalloproteinase-3 (TIMP-3), a recently identified member of the human TIMP family. When human ESC were cultured in the presence of P for 6 days, the induction of TIMP-3 messenger RNA (mRNA) expression was observed by Northern blotting. In contrast, the marked induction of PRL mRNA expression and morphological changes were observed after 9 days of culture. P-induced TIMP-3 mRNA expression was dose dependent, and this induction was inhibited by the antiprogestin RU486. Estrogen did not induce TIMP-3 mRNA expression under similar conditions. In situ hybridization analysis of endometria from nonpregnant women revealed that the TIMP-3 mRNA expression was restricted to predecidualized stromal cells. At the feto-maternal interface, TIMP-3 expression was observed in fetal extravillous trophoblasts that had invaded the maternal decidual tissues as well as in the maternal decidual cells. These findings suggest that TIMP-3 is a sensitive indicator of ESC decidualization, and that the induction of TIMP-3 expression in decidual cells and trophoblasts may be important in the regulation of trophoblast invasion.

Requirement for transglutaminase in progesterone-induced decidualization of human endometrial stromal cells.

Differentiation of endometrial stromal cells (decidualization) is essential for embryo implantation and maintenance of pregnancy. By sequential complementary DNA subtractive hybridization, one of the messenger RNAs (mRNA) induced by progesterone in human endometrial stromal cells decidualized in vitro was identified as that of a tissue transglutaminase type II (TGase). TGase mRNA was induced within 6 h after the addition of progesterone to the culture, and the effect was dose dependent. Both the TGase inhibitor monodansylcadaverine and oligodeoxynucleotide complementary to the TGase mRNA inhibited the decidualization, as assessed by PRL production and morphological transformation. Expression of TGase mRNA in human decidua and endometria exposed to high levels of progesterone in vivo was demonstrated by Northern blotting and in situ hybridization. These data suggest that TGase is necessary for the decidualization of human endometrial stromal cells and that clarification of the mechanism of action of TGase will facilitate further insight into the diagnosis and treatment of infertility.

Progesterone enhances interleukin-15 production in human endometrial stromal cells in vitro.

Interleukin-15 (IL-15) is a novel cytokine that stimulates lymphocyte proliferation and migration via a trimeric receptor sharing the ss and gamma signal-transducing chains with the IL-2 receptor. It is suggested that IL-15 is involved in regulating the proliferation and differentiation of uterine natural killer cells. In the human endometrium, we have recently reported that IL-15 messenger ribonucleic acid (mRNA) levels significantly increased during the secretory phase compared with those during the proliferative phase. In this study we investigated whether the female sex steroids progesterone (P) and estradiol (E(2)) regulate IL-15 messenger RNA (mRNA) and the secretion in human endometrial stromal cells (ESC) in vitro. Northern blot analyses revealed a significant increase in IL-15 mRNA levels in ESC treated with P alone or E(2) plus P compared with vehicle. Furthermore, P is a potent inducer of IL-15 mRNA expression in ESC in a dose-dependent manner. On the other hand, E(2) alone did not increase IL-15 mRNA expression. By enzyme-linked immunosorbent assay, IL-15 protein secretion was stimulated by P and further enhanced by combined treatment with E(2) and P, whereas E(2) alone was ineffective. It is suggested that IL-15 is deeply involved in the hormonal control of the human endometrium by P and E(2).

Androgens induce prolactin production by human endometrial stromal cells in vitro.

Although there is a significant quantity of androgens in the endometrium, the function of these hormones has not been clarified, except for being estrogen precursors. Human endometrial stromal cells (ESC) were cultured in the presence of testosterone (T) and 5 alpha-dihydrotestosterone. Following culture, prolactin (PRL), a biochemical marker of stromal cell differentiation (decidualization) which is produced by ESC, was examined. T induced PRL production in a time- and dose-dependent manner, as reported previously for progesterone (P) stimulation. In addition, 5 alpha-dihydrotestosterone, which cannot be converted to estrogens, similarly induced PRL production. T in combination with P enhanced PRL production in cultured ESC significantly more than either P or T stimulation alone. A specific androgen receptor blocker, flutamide, when added to cultures containing T, inhibited PRL production in a dose-dependent manner, but did not affect the production of PRL induced by P. These results indicate that in vitro PRL production by human ESC is induced not only by P, but also by androgens through specific receptors and further suggest that androgens play an important role in human endometrial differentiation.

Interleukin-1 inhibits in vitro decidualization of human endometrial stromal cells.

Interleukin-1 (IL-1), a critical cytokine for the initiation of the immune response to infection or antigenic challenge, is known to also possess a variety of biological functions outside the immune system. We examined whether IL-1 could affect the decidualization of human endometrial stromal cells (ESC), a conspicuous part in the process of implantation, by assessing PRL production and morphological transformation in an in vitro system. Purified human ESC were cultured in the presence of progesterone (P) with or without the addition of IL-1. IL-1 markedly suppressed the induction of PRL production by P in a dose-dependent manner. The morphological decidualization of ESC in response to P was also inhibited by IL-1. This report demonstrates for the first time the possibility that IL-1 blocks decidualization, the functional differentiation of human endometrial stromal cells in response to ovarian steroids.