Kaori Koga

Toll-Like Receptors at the Maternal–Fetal Interface in Normal Pregnancy and Pregnancy Disorders

Citation Koga K, Mor G. Toll‐like receptors at the maternal–fetal interface in normal pregnancy and pregnancy disorders. Am J Reprod Immunol 2010

Activation of TLR3 in the trophoblast is associated with preterm delivery.

Problemu2002 Toll‐like receptors (TLRs) recognize conserved sequences on the surface of pathogens and trigger effector cell functions. Previously, we described the expression of TLR3 by human trophoblast and their ability to respond to (Poly[I:C]). Here we evaluate the effect of Poly[I:C] on mouse pregnancy and characterize the local and systemic response.

TLR6 Modulates First Trimester Trophoblast Responses to Peptidoglycan

Intrauterine bacterial infections are a well-established cause of pregnancy complications. One key observation in a number of abnormal pregnancies is that placental apoptosis is significantly elevated. First trimester trophoblast cells are known to express TLR1 and TLR2 and to undergo apoptosis following exposure to Gram-positive bacterial peptidoglycan (PDG). Thus, the objectives of this study were to determine whether PDG-induced pregnancy complications are associated with placental apoptosis and to characterize the cellular mechanisms involved. We have demonstrated, using an animal model, that delivery of PDG to pregnant mice early in gestation resulted in highly elevated placental apoptosis, evidenced by trophoblast M-30 and active caspase 3 immunostaining. Using an in vitro model of human first trimester trophoblasts, apoptosis induced by PDG was found to be mediated by both TLR1 and TLR2 and that this could be blocked by the presence of TLR6. Furthermore, in the presence of TLR6, exposure to PDG resulted in trophoblast NF-κB activation and triggered these cells to secrete IL-8 and IL-6. The findings of this study suggest that a Gram-positive bacterial infection, through TLR2 and TLR1, may directly promote the elevated trophoblast cell death and that this may be the underlying mechanism of pregnancy complications, such as preterm delivery. Furthermore, the expression of TLR6 may be a key factor in determining whether the response to PDG would be apoptosis or inflammation.

Lymphocytes in Endometriosis

Citation Osuga Y, Koga K, Hirota Y, Hirata T, Yoshino O, Taketani Y. Lymphocytes in Endometriosis. Am J Reprod Immunol 2011; 65: 1–10

Toll-like receptors and pregnancy: Trophoblast as modulators of the immune response

During normal pregnancy, the decidua is populated by a variety of leucocytes; however, cells of the innate immune system seem to dominate this tissue. Their presence suggests that the innate immune system is not indifferent to the fetus and has been associated with a response of the maternal immune system to the ‘semi‐allograft’ fetus. New evidences, however, indicate that these immune cells are critical for decidual and trophoblast development rather than induction of tolerance. We hypothesized that during implantation, an inflammatory environment is necessary for the attachment and invasion of the blastocyst. The existence of an ‘inflammatory‐mediated embryo implantation’ condition is dependent on the proper ‘education’ of the innate immune system which we propose is mediated by the trophoblast. Here we postulate that trophoblast cells successfully orchestrate their inflammatory environment and regulate immune cells differentiation and activation through Toll‐like receptors (TLR). We will describe potential functions of TLR in trophoblast cells, their recognition and response to microorganisms, and their involvement in innate immunity.

Post-operative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision

BACKGROUNDnThe aim of this study was to evaluate the impact of post-operative oral contraceptives (OCs) use on the rate of recurrence after laparoscopic excision of ovarian endometrioma.nnnMETHODSnIn May 2005, we introduced a post-operative OC recommendation for patients treated with laparoscopic excision of endometrioma. That is, at the time of the operation, we provided each patient with information about OC, known and possible benefits and risks and let her decide whether to take OC. A retrospective cohort study included 87 patients who underwent a laparoscopy after May 2005. The endometrioma recurrence rate at 24 months was compared between those who used OC for the entire follow-up period OC (n = 34) and all of the others (n = 53). We also performed logistic regression analysis to identify variables associated with recurrence. A before-after study included another 224 patients who underwent a laparoscopy before May 2005 and compared the recurrence rate before and after introduction of the post-operative OC recommendation.nnnRESULTSnThe recurrence rate in those who used OC for the entire period was significantly lower than in the others group (2.9 versus 35.8%, relative risk 0.082, 95% CI 0.012-0.58, P < 0.001). Post-operative OC was determined as an independent variable associated with lower recurrence (OR 0.054, 95% CI 0.007-0.429, P < 0.001). The overall recurrence rate in patients who underwent laparoscopy after the introduction of the post-operative OC recommendation was significantly lower than that in patients who received laparoscopy before the introduction (18.6 versus 33.1%, relative risk 0.56, 95% CI 0.32-0.97, P < 0.05).nnnCONCLUSIONSnPost-operative OC use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. This information will help in appropriate planning of pre- and post-operative management.

Elevated serum soluble fms-like tyrosine kinase 1 (sFlt1) level in women with hydatidiform mole

OBJECTIVEnTo show soluble fms-like tyrosine kinase 1 (sFlt1) levels in sera from patients with hydatidiform mole, which is known to predispose women to severe early-onset preeclampsia.nnnDESIGNnComparative study.nnnSETTINGnUniversity hospital and surrounding community hospitals.nnnPATIENT(S)nSeven women with pathologically diagnosed complete hydatidiform mole (mole group), 21 gestational- and maternal-age-matched women who did not develop any pregnant complication during their pregnancy (control group), and eight women who subsequently developed preeclampsia (preclinical preeclampsia group).nnnINTERVENTION(S)nBlood samples were taken before and after evacuations of hydatidiform mole.nnnMAIN OUTCOME MEASURE(S)nConcentrations of sFlt1 and free placental growth factor (PlGF) in serum were measured by ELISA.nnnRESULT(S)nSerum sFlt1 concentrations were significantly higher in the mole group compared with the control group and the preclinical preeclampsia group. In contrast, serum free PlGF concentrations were significantly lower in the mole group. In the mole group, there was a significant negative correlation between sFlt1 and PlGF serum concentrations. After the evacuation of hydatidiform mole, the level of serum sFlt1 decreased dramatically.nnnCONCLUSION(S)nElevated levels of sFlt1 were noted in molar gestations and may play in a role in early-onset preeclampsia reported in such pregnancies.

Activin-A is induced by interleukin-1β and tumor necrosis factor-α and enhances the mRNA expression of interleukin-6 and protease-activated receptor-2 and proliferation of stromal cells from endometrioma

OBJECTIVEnTo examine the regulation and the function of activin-A in stromal cells derived from endometrioma.nnnDESIGNnMolecular studies.nnnSETTINGnUniversity research laboratory.nnnPATIENT(S)nEndometrioma stromal cells (EoSC) were obtained from 28 patients with ovarian endometrioma undergoing laparoscopy.nnnINTERVENTION(S)nEoSC were cultured with inflammatory stimuli or recombinant activin-A, followed by RNA extraction.nnnMAIN OUTCOME MEASURE(S)nActivin mRNA expression was evaluated by real-time reverse transcription-polymerase chain reaction (RT-PCR), and activin-A concentration of supernatant of cultured EoSC was evaluated by ELISA. Also, the effect of activin-A on EoSC was evaluated with real-time RT-PCR and cell proliferation assay.nnnRESULT(S)nInflammatory stimuli, interleukin (IL) -1β, and tumor necrosis factor (TNF) -α induced inhibin/activin-βA subunit mRNA and activin-A protein expression in EoSC. Additionally, activin-A enhanced EoSC proliferation and increased the expression of IL-6 and protease-activated receptor (PAR)-2 mRNA.nnnCONCLUSION(S)nAn in vitro study revealed that activin-A, which is induced by IL-1β or TNF-α, might promote endometriosis by stimulating IL-6 and PAR-2 mRNA expression and increasing the proliferation of EoSC.

Dienogest, a new conservative strategy for extragenital endometriosis: a pilot study

Extragenital endometriosis severely impairs the quality of life for affected women but its standard management has not yet been well established because of its relatively low incidence. As extragenital organs, intestine, followed by urinary tract, is the most common place affected by endometriosis, for which surgical treatment is sometimes difficult and accompanied by severe complications. Recently, dienogest, a novel progestin, has emerged as a new alternative for endometriosis, especially for endometriosis-associated pain. In this report, we presented four cases with rectosigmoidal and one with bladder endometriosis, treated with oral 2 mg/day dienogest for over 6 months. For all cases, the measurable extragenital lesions exhibited the reduction in their size after 10 to 11 months of use, accompanied with immediate relief of subjective symptoms related with extragenital lesions. This report suggests that dienogest can be a novel conservative alternative for extragenital endometriosis.

TGF-β1 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6

BACKGROUNDnProteinase-activated receptor 2 (PAR2) is a G-protein-coupled receptor that is activated by several serine proteases. PAR2 activation in endometriotic stromal cells (ESCs) has been implicated in the development of endometriosis but the regulatory mechanism of PAR2 expression in ESC is unknown. Our objective was to study the mechanism by which PAR2 expression may be regulated in endometriotic lesions.nnnMETHODSnPrimary cultures of ESCs were treated with transforming growth factor-β (TGF-β) 1, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the expression of PAR2 was examined by real-time quantitative PCR. ESCs pretreated with or without TGF-β1 were treated with PAR2 agonist peptide (PAR2AP) and the secretion of the pro-endometriotic cytokine, IL-6, was measured using a specific enzyme-linked immunosorbent assay. Effects of TGF-β type 1 inhibitor, SB431542, and PAR2 small interfering RNA (siRNA) on the TGF-β1 stimulation of PAR2 gene expression and PAR2AP-induced IL-6 secretion were also evaluated. To study intracellular signaling, effects of inhibitors of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) and of Smad4 siRNA on the TGF-β1-induced PAR2 gene expression were studied.nnnRESULTSnOnly TGF-β1, but neither TNF-α nor IL-1β, increased gene expression of PAR2. Activation of PAR2 with PAR2AP increased the secretion of IL-6 from ESCs. As expected, TGF-β1 pretreatment dose-dependently enhanced the PAR2AP-induced increase in IL-6 secretion from ESCs. Treatment of ESCs with the TGF-β type 1 inhibitor, SB431542, inhibited both TGF-β1-stimulation of PAR2 gene expression and PAR2AP-induced IL-6 secretion. Transfection of ESCs with PAR2 siRNA produced a similar inhibition of IL-6 secretion. The TGF-β1-induced increase in PAR2 gene expression was repressed by inhibition of p38 MAPK, p42/44 MAPK or PI3K, but not by knockdown of Smad4 expression.nnnCONCLUSIONSnIn view of significant roles of PAR2 and IL-6 in endometriosis, the TGF-β1-induced increase in PAR2 expression may be an elaborate mechanism that augments the progression of the disease.