Andrea Steinborn

Elevated placental cytokine release, a process associated with preterm labor in the absence of intrauterine infection*

Objective To investigate the role of cytokines in normal term and preterm labor in the absence of intrauterine infection. Methods Cytokine (interleukin [IL]-1β, IL-6 and tumor necrosis factor-α [TNF-α]) release was estimated from placental and decidual cell cultures from 22 nonlaboring women at term with cesarean deliveries, 18 women with spontaneous labor at term, and 21 women with preterm labor (19-36 weeks gestation) who delivered vaginally or by cesarean, according to gestational age. Eight of 21 women delivering preterm had clinical evidence of intrauterine infection, and 13 were not infected. Results Placental cell cultures obtained from women with spontaneous term labor released significantly larger amounts of cytokines (median: IL-1β 6450 pg/mL, IL-6 1821 ng/mL, and TNF-α 13,506 pg/mL) compared with placental cell cultures from nonlaboring women at term (median: IL-1β 2602 pg/mL, IL-6 993 ng/mL, TNF-α 3475 pg/mL; P < .02). Placental cells from women delivering preterm with intrauterine infection did not produce significantly different amounts of cytokines (median: IL-1β 3929 pg/mL, IL-6 1084 ng/mL, TNF-α 2847 pg/mL) when compared with those of nonlaboring women at term, whereas placental cells from uninfected women delivering preterm produced significantly larger amounts of cytokines (median: IL-1β 22,903 pg/mL, IL-6 1899 ng/mL, TNF-α 15,005 pg/mL; P < .01) than cells from nonlaboring women at term. Cytokine release from decidual cell cultures was similar in all groups tested. Conclusion In the absence of intrauterine infection, preterm labor was associated with elevated placental cytokine release.

Immunmodulating cytokines induce term and preterm parturition

The aim of our study was to investigate if cytokines, which are able to cause preterm delivery is case of intraamniotic infection, also participate in the mechanisms of normal term labor. Therefore we estimated cytokine concentrations in cercicovaginal secretions of 96 patients, divided into four different collectives. In collective A (women with spontaneous term labor) cytokine concentrations raised from a median level of 278 pg/ml for Il-1 beta and 263 pg/ml for Il-6 in early term labor to a median level of 3351 pg/ml for Il-1 beta and 39,442 pg/ml for Il-6 at complete cervical dilatation. TNF-alpha-exclusively appeared after spontaneous rupture of fetal membranes. In collective B and C (women with preterm rupture of fetal membranes) cytokine concentrations declined from a maximum level of 1425 pg/ml for TNF-alpha, 12,982 pg/ml for Il-1 beta and 29,727 pg/ml for Il-6 soon after preterm rupture of membranes to a minimum level of 93 pg/ml for TNF-alpha, 851 pg/ml for Il-1 beta and 780 pg/ml for Il-6 with remission of labor in case of successful tocolytic treatment. High concentrations reappeared with the onset of labor, unresponsive to tocolysis. In collective D (women with intact membranes) TNF-alpha was not detectable and Il-1 beta and II-6 appeared exclusively in the presence of labor. Our results suggest, that normal term labor may be controlled by biochemical processes, similar to infection-associated signal transduction, which is commonly accepted to induce preterm labor.

Identification of placental cytokine-producing cells in term and preterm labor.

Objective To determine if the production of proinflamma-tory cytokines by placentally derived macrophages changes with term and preterm labor and to examine if changes in antigen expression of these cytokines can be detected by immunohistologic methods. Methods Enzymatically dispersed placental cell suspensions of the trophoblastic villi, obtained from 16 women with spontaneous term delivery, 16 women with elective cesarean delivery without any labor, and 22 preterm delivering women with labor unresponsive to tocolysis, were fractionated by magnetic-associated-cell-sorting, on the basis of CD11b-antigen expression. Positively and negatively sorted cell fractions were cultured and concentrations of interleukin-6, interleukin-1β, and tumor-necrosis-factor-α were measured in the culture supenatants. Immunohistologic staining was used for identification of cytokine-producing cells within placental tissues. Results Positively sorted cells obtained from term (median 2027 pg/mL, P = .037) and preterm (median 3628 pg/mL, P = .001) laboring women produced significantly elevated amounts of tumor-necrosis-factor-α compared with nonlaboring (median 1088 pg/mL) women at term. Negatively sorted cell fractions obtained from term (median interleukin-1β 162 pg/mL, P = .031, median interleukin-6 3134 pg/mL, P = .004) and preterm (median interleukin-1β 934 pg/mL, P = .003, median interleukin-6 5695 pg/mL, P = .001) laboring women produced significantly elevated amounts of interleukin-1β and interleukin-6 compared with nonlabor-ing (median interleukin-1β 29 pg/mL, median interleukin-6 135 pg/mL) women at term. Immunohistologic staining revealed that tumor-necrosis-factor-α activity was localized in isolated stromal cells, whereas interleukin-1β and interleukin-6 were predominantly found in endothelial cells within placental; villi. Conclusion The source of labor-associated release of tumor-necrosis-factor-α from placental tissues are macrophages, whereas interleukin-1β and interleukin-6 are released from placental endothelial cells.

Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal carcinoma in situ, breast cancer, and resident macrophages of normal breast tissue.

Macrophages concentrate urokinase‐type plasminogen activator (uPA) at the cell surface by expressing urokinase receptors (uPAR) in order to focus the pericellular space plasminogen‐dependent proteolysis important in matrix remodeling and cell movement. This study examines the uPAR levels of tumor‐associated macrophages (TAM) of invasive breast carcinomas, of TAMs from ductal carcinoma in situ (DCIS) and of macrophages derived from normal (non‐tumor) breast tissue. TAMs from invasive breast carcinomas (n = 30), from DCIS (n = 12), and macrophages from normal breast tissue (n = 30) were cultured and immunocytochemically phenotyped by using a panel of antibodies. Urokinase receptor levels were determined by Western blot analysis and in cell‐free supernatants by enzyme‐linked immunosorbent assay. Urokinase receptor cell surface fluorescence intensity was determined by FACS and by confocal laser scan microscopy. Urokinase‐receptor mRNA was detected by in situ hybridization. TAMs of invasive breast carcinomas and of DCIS possess significantly elevated uPAR levels compared with macrophages derived from normal breast tissue. Conclusions: activated macrophages with elevated uPAR levels belong to inflammatory areas in close vicinity of infiltrating and non‐infiltrating (DCIS) tumor cells. Blood monocytes that possess elevated uPAR‐levels may be selectively recruited from the bloodstream to inflammatory sites close to carcinoma cells, and/or breast cancer and precursor lesions may induce elevated uPAR‐levels in TAMs by paracrine interactions. J. Leukoc. Biol. 66: 40–49; 1999.

Placental Abruption Is Associated with Decreased Maternal Plasma Levels of Soluble HLA-G

During pregnancy the fetus represents a semi-allograft. Both membrane-bound and soluble forms of the nonclassic human leukocyte antigen (HLA)-G protect the fetus from maternal immune attack. To assess the relevance of soluble HLA-G (sHLA-G) levels in the maternal circulation for the occurrence of characteristic pregnancy disorders, we analyzed sHLA-G plasma levels of women with normal and pathological pregnancies. Compared to normal pregnancy, significantly increased sHLA-G levels were detected in women delivered preterm because of intrauterine activation (uncontrollable labor, rupture of fetal membranes, cervical insufficiency) and women with Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome. Contrary to these disorders, the sHLA-G levels in women with placental abruption were more than three times lower than in normal pregnancy (p < 0.0001). Nonparametric discriminant analysis showed that women with sHLA-G levels below 9.95 ng/mL had a relative risk of 7.12 for the development of placental abruption during further course of pregnancy. These results suggest that the occurrence of pregnancy-associated diseases is strongly influenced by maternal sHLA-G plasma levels.

3D Real-Time Imaging of the Fetal Heart

Objective: The aim of this study was to evaluate the clinical utility of a novel 3D scanner system for real-time 3D fetal echocardiography. Method: In a prospective study, 13 single, healthy 20- to 24-week-old fetuses were examined with conventional 2D and real-time 3D echocardiography. The visualization rates and imaging quality of standard cardiac views were compared between both methods. Results: The visualization rates of standard cardiac planes were found to be slightly increased and more easily obtainable in 3D imaging whereas the image quality showed better results with conventional 2D echocardiography. Conclusion: Our data show that real-time 3D fetal echocardiography can be considered a useful tool in the evaluation of the fetal heart with the necessity for further refinement of the resolution quality

SIGNAL FOR TERM PARTURITION IS OF TROPHOBLAST AND THEREFORE OF FETAL ORIGIN

Up to now we know, that cytokines are key intermediates in the mechanisms, responsible for intrauterine activation in case of intra amniotic infection. The aim of our study was to investigate the role of cytokine- and prostaglandin production in normal term labor. Release of Il-6, Il-1 beta, TNF-alpha, PGE2, PGF2 alpha, was monitored in vaginal secretions originating from uterine cavity, cervix and vagina during normal course of labor. Cells from fetal membranes, decidua and villous trophoblast, obtained from placentas of patients after spontaneous delivery (n = 12), or without labor, after elective cesarean section (n = 12), were cultured, in order to identify cytokine and prostaglandin producing cells. In all cases, term labor and parturition was associated with strongly elevated cytokine- and prostaglandin concentrations in cervical secretions. Cell culture experiments clearly demonstrated, that cells from villous trophoblast, cultured after spontaneous delivery produced significantly more cytokines and prostaglandins than cells form villous trophoblast, cultured after elective cesarean section. Cells from fetal membranes also produced more Il-6 and PGE2 after labor. In contrast to that, cells from decidua produced similar amounts of cytokines and prostaglandins before and after spontaneous term labor. Therefore we conclude, that the signal for term labor and delivery is of trophoblast and so of fetal origin.

Evaluation of Two-Dimensional versus Three-Dimensional Ultrasound in Obstetric Diagnostics: A Prospective Study

Objectives: We aimed to find answers to the following questions: What are the technical and biological prerequisites for easily obtainable three-dimensional (3D) images? What are the visualization rates for various fetal organ systems? What is the potential for assessing fetal malformations? What are the psychological effects of 3D imaging on the expectant mothers? Methods: Between January and June 1998, 433 pregnant women were prospectively examined with two-dimensional (2D) and 3D sonography. Results: 3D visualization in healthy fetuses was inferior in quality to 2D visualization, which also accounted for the comparison of 3D imaging versus 2 D imaging among fetuses affected with malformations. In only 1 case did 3D imaging yield a slightly better description of the given malformation. This did not result in a different therapeutical approach. Concerning the psychological effect of 3D imaging, a marked approval of the 3D method was recorded. Conclusions: These results show that the image information acquired by 3D ultrasound technology is nearly always inferior to the image information obtained by conventional 2D imaging. 3D imaging can be useful for specific malformations under the condition that these examinations be performed in specific ultrasound departments. Thus, a clearly defined range of indications can be assigned to 3D imaging.