Evidence for participation of uterine natural killer cells in the mechanisms responsible for spontaneous preterm labor and delivery.

OBJECTIVE: The purpose of this study was to determine in a mouse model whether uterine natural killer (uNK) cell cytotoxic activation induces infection/inflammation-associated preterm labor and delivery. STUDY DESIGN: Wild type or interleukin (IL)-10(-/-) mice were injected intraperitoneally with lipopolysaccharide on gestational day 14. Mice were either killed for collection of uteroplacental tissue, spleen, and serum or allowed to deliver. Uteroplacental tissue was used for histology and characterization of uNK cells. RESULTS: Low-dose lipopolysaccharide treatment triggered preterm labor and delivery in IL-10(-/-), but not wild type mice, in a manner independent of progesterone levels. Preterm labor and delivery in IL-10(-/-) mice was associated with an increased number and placental infiltration of cytotoxic uNK cells and placental cell death. Depletion of NK cells or tumor necrosis factor (TNF)-alpha neutralization in these mice restored term delivery. Furthermore, TNF-alpha neutralization prevented uNK cell infiltration and placental cell apoptosis. CONCLUSION: The uNK cell-TNF-alpha-IL-10 axis plays an important role in the genesis of infection/inflammation-induced preterm labor/delivery.

Further delineation of interstitial chromosome 6 deletion syndrome and review of the literature.

Interstitial deletions of chromosome 6q are a relatively rare finding. Deletions have ranged from the loss of a single band to larger deletions spanning multiple bands. The clinical phenotype varies, but some features commonly seen include cardiac anomalies, hypotonia, facial dysmorphism and mental retardation. To further delineate the syndrome, we report an infant with facial dysmorphism, ectrodactyly and tetralogy of Fallot owing to interstitial deletion 6q16.1-6q22.32. On array comparative genomic hybridization analysis, the deletion spanned from the 93 377 323rd base to the 127 650 582nd base on chromosome 6 [coordinates are based on Human Mar. 2006 (hg18) assembly of International Human Genome Sequencing Consortium]. A literature review identified 16 additional cases with overlapping interstitial deletions of chromosome 6q between q13 and q23.1. Genotype-phenotype correlations are considered.

Variations in cervical IL-10 and IL-8 concentrations throughout gestation in normal pregnancies.

PROBLEM: Data regarding cervical interleukin 18 (IL-8) and IL-10 concentrations during pregnancy is limited. METHOD OF STUDY: This was a cross sectional study of healthy pregnant women. Specimens were collected from the cervical os secretions. IL-8 and IL-10 levels were measured by using enzyme-linked immunosorbent assay. Median (range) cytokine concentrations were derived for each trimester and compared across trimesters. The relationship between gestational age and cytokine levels was assessed by regression analysis. The mean of the ratios of IL-8 to IL-10 was compared in each trimester using anova. RESULTS: The median (range) IL-8 concentrations in cervical secretions were in pg/mL: 1562 (1210-4100), 2460 (1047-4688), 3660 (1451-4748) (P < 0.0021); the median (range) IL-10 concentrations in cervical secretions were in pg/mL: 38.3 (6.8-227.9), 10.9 (0-263.3), 9.5 (0-35.6); the mean IL10/IL-8 x 100 (+/- standard deviation) concentrations were: 3.33 +/- 0.65, 1.47 +/- 0.41, 0.38 +/- 0.52 (P = 0.0035) during the first, second and third trimesters, respectively. CONCLUSION: The patterns of cervical IL-8 concentration is inversely related to gestational age, and the ratio of IL-10/IL-8 decreases with advancing gestation.

Uterine NK cells mediate inflammation-induced fetal demise in IL-10-null mice.

Specialized NK cells are recruited in high numbers to the mammalian embryo implantation sites, yet remain pregnancy compatible. It is not well understood whether uterine NK (uNK) cells become adversely activated and mediate fetal demise, a common complication of early pregnancy. In this study we show that mating of IL-10(-/-) mice resulted in fetal resorption or intrauterine growth restriction in response to very low doses of LPS. Pregnancy in congenic wild-type mice was normal even at 10-fold higher LPS doses. Fetal resorption in IL-10(-/-) mice was associated with a significant increase in uNK cell cytotoxic activation and invasion into the placenta. Depletion of uNK cells, TNF-alpha neutralization, or IL-10 administration rescued pregnancy in LPS-treated IL-10(-/-) animals. Our results identify an immune mechanism of fetal demise involving IL-10 deficiency, NK cells, and inflammation. These results may provide insight into adverse pregnancy outcomes in humans.

Evidence for cyclin D3 as a novel target of rapamycin in human T lymphocytes.

The immunosuppressant rapamycin has been shown to inhibit G(1)/S transition of the cell cycle. This inhibition is thought to be mediated by maintenance of the threshold levels of cyclin-dependent kinase (CDK) inhibitor p27(Kip1) (p27) and inhibition of p70 s6 kinase (p70(s6k)). However, recent evidence suggests that cells still remain sensitive to rapamycin in the absence of functional p27 or p70(s6k). Here, we show that rapamycin represses cyclin D3 levels in activated human T lymphocytes with no inhibitory effects on cyclin D2. Furthermore, rapamycin elicits similar cyclin D3 modulatory effects in B lymphocytes. The overall effect of rapamycin on cyclin D3 leads to impaired formation of active complexes with Cdk4 or Cdk6 and subsequent inhibition of cyclin D3/CDK kinase activity. Decrease in cyclin D3 protein levels is due to translational repression and not due to attenuated transcription of the cyclin D3 gene. Importantly, stable overexpression of cyclin D3 (2-2.5 fold) in Jurkat T cell transfectants renders them resistant to lower doses (1-10 ng/ml) of rapamycin. These results point to a critical role of cyclin D3 in rapamycin-mediated immunosuppressive effects in T cells and cell cycle regulation in lymphocytes in general.

Expression of multiple drug resistance conferring proteins in normal Chinese and Caucasian small and large intestinal tissue samples.

Multidrug resistance conferring proteins (MDRCP) are ATP-binding cassette (ABC) transporters known to significantly influence the absorption, distribution, metabolism, and elimination (ADME) and toxic behavior of many therapeutic agents. Research in the pharmacogenomics area has suggested that mutations and variable expression patterns of these MDCRPs may exist in tissue samples from different ethnic groups. The goal of this study was to examine the expression of P-glycoprotein (PGP), sister of PGP (S-PGP), multidrug resistance protein 3 (Mdr3), multidrug resistance like proteins 1-5 (MRP 1-5), and lung resistance associated protein (LRP) in tissue slides and protein lysates derived from normal adult small or large intestines of Caucasian or Chinese origin. Our results demonstrated ubiquitous expression of PGP, MRP 1, MRP 4, and LRP in the small and large intestinal epitheliums originating from both Caucasian and Chinese origin. S-PGP, Mdr3, MRP 2, and MRP 3 exhibited variable expression in the tissue slides and protein lysates derived from the Chinese and Caucasian small and large intestines. MRP 5 was not observed in any of the samples studied. The results suggest that MDCRPs may have distinct expression profiles in the small and large intestines that potentially vary with genetic background. These studies provide a foundation for further investigations to verify these findings across a wider number of patients of different ethnic backgrounds.