Clinical studies suggest that intrauterine infection is a major medical factor association with preterm labor (PTL) in women. We hypothesize that PTL results from the synergistic interplay between signals (e.g. EGF) and inflammatory cytokines (e.g. IL-I, TNF-alpha, TGF-beta), elaborated into the decidua and/or amniotic cavity following a maternal immune response to bacterial colonization. We postulate that cytokines modulate the action of EGF by sensitizing amnion cells and, thereby, cause a robust prostaglandin synthetic response leading to premature uterine contractility and cervical dilatation. This research proposal will test the hypothesis that cytokines modulate EGF action in amnion cells using the amnion-derived cell line WISH as an in vitro model system. The EGF signal transduction cascade (i.e. receptor expression, phospholipase A2-mediated arachidonic acid release, and cyclooxygenase activation/induction) will be examined to determine whether cytokine treatment alters EGF action at one or more of these key regulatory points.
Aim 1 will address whether IL-1beta, TNF- alpha and TGF-beta, which are associated with intrauterine infection- mediated PTL can alter EGF receptor expression by (i) inducing rapid EGF receptor internalization and recycling to the cell surface and (ii) increasing the expression of EGF receptor mRNA in amnion cells.
Aim 2 will examine whether IL-1beta, TNF-alpha and TGF-beta can modulate phospholipase A2 activity and/or induction either independently or in combination with EGF in amnion cells. This question will be addressed by measuring the specific activity, PLA2 protein expression and PLA2 mRNA expression in cytokine and EGF treated cells.
Aim 3 will examine whether IL-1beta, TNF-alpha and TGF-beta can modulate cyclooxygenase activity and/or induction either independently or in combination with EGF in amnion cells. The specific activity for cyclooxygenase, and cyclooxygenase protein and mRNA expression will be measured to address this aim. Elucidating the potential control points for cytokine-mediated alterations in EGF action in amnion cells may provide a readily testable model system for understanding the biochemical details of premature activation of the prostaglandin cascade in relation to PTL.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HD028360-01A2
Application #
2201025
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1994-02-01
Project End
1999-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Ohio State University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Xie, Y; Yang, S T; Kniss, D A (2001) Three-dimensional cell-scaffold constructs promote efficient gene transfection: implications for cell-based gene therapy. Tissue Eng 7:585-98
Kniss, D A; Rovin, B; Fertel, R H et al. (2001) Blockade NF-kappaB activation prohibits TNF-alpha-induced cyclooxygenase-2 gene expression in ED27 trophoblast-like cells. Placenta 22:80-9
Smith, A N; Carter, Q L; Kniss, D A et al. (2001) Characterization of a TGFbeta-responsive human trophoblast-derived cell line. Placenta 22:425-31
Kniss, D A (1999) Cyclooxygenases in reproductive medicine and biology. J Soc Gynecol Investig 6:285-92
Perkins, D J; Kniss, D A (1999) Blockade of nitric oxide formation down-regulates cyclooxygenase-2 and decreases PGE2 biosynthesis in macrophages. J Leukoc Biol 65:792-9
McKenna, D S; Samuels, P; Zimmerman, P D et al. (1998) Interleukin-1 alpha, epidermal growth factor, and transforming growth factor-beta exhibit differential kinetics on endothelin-1 synthesis in amnion cells. J Soc Gynecol Investig 5:25-30
Perkins, D J; Kniss, D A (1997) Rapid and transient induction of cyclo-oxygenase 2 by epidermal growth factor in human amnion-derived WISH cells. Biochem J 321 ( Pt 3):677-81
Imseis, H M; Zimmerman, P D; Samuels, P et al. (1997) Tumour necrosis factor-alpha induces cyclo-oxygenase-2 gene expression in first trimester trophoblasts: suppression by glucocorticoids and NSAIDs. Placenta 18:521-6
Perkins, D J; Kniss, D A (1997) Tumor necrosis factor-alpha promotes sustained cyclooxygenase-2 expression: attenuation by dexamethasone and NSAIDs. Prostaglandins 54:727-43
Swaisgood, C M; Zu, H X; Perkins, D J et al. (1997) Coordinate expression of inducible nitric oxide synthase and cyclooxygenase-2 genes in uterine tissues of endotoxin-treated pregnant mice. Am J Obstet Gynecol 177:1253-62

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