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Inflammatory Cytokine and Thrombin Regulation of Interleukin-8 and Intercellular Adhesion Molecule-1 Expression in First Trimester Human Decidua

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine (C.J.L., M.P., G.K., E.K., H.K., F.S.), New Haven, Connecticut 06510; Department of Oncology, Biogen, Inc. (L.A.K.), Cambridge, Massachusetts 02142; Department of Obstetrics and Gynecology, New York University School of Medicine (R.M.), New York, New York 10016; and Department of Pathology, Weill Medical College of Cornell University (R.N.B.), New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Frederick Schatz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, Room 335 FMB P.O. Box 208063, New Haven, Connecticut 06510. E-mail: frederick.schatz{at}yale.edu.

Context: Decidual neutrophil infiltration complicates spontaneous abortions associated with inflammation and hemorrhage. Transendothelial neutrophil migration into inflamed tissues involves IL-8-mediated chemoattraction, then neutrophil attachment to endothelial cell-expressed intercellular adhesion molecule-1 (ICAM-1).

Objective: The aim of this study was to assess IL-8 and ICAM-1 regulation in decidual inflammation and hemorrhage; the effects of the proinflammatory cytokines, TNF, IL-1ß and the hemostatic, proinflammatory cytokine thrombin were measured on IL-8 expression in first trimester decidual cells (DCs), and ICAM-1 immunostaining was compared in normal, inflamed, and hemorrhagic first trimester decidua.

Design: Immunohistochemistry of human decidua and in vitro treatment of human decidual cells were performed

Setting: The study was conducted at the Academic Medical Center.

Intervention:. DCs were passaged until they were leukocyte-free (CD45 free by FACS), then were incubated with estradiol or medroxyprogesterone acetate alone or with TNF or IL-1ß or thrombin. Normal, inflamed, and hemorrhagic decidua were immunostained for ICAM-1 and the neutrophil marker CD14.

Main Outcome Measure: ICAM-1 immunostaining was performed in decidua. IL-8 levels in DC-conditioned media were assessed by ELISA and immunoblotting; IL-8 mRNA levels were measured by quantitative RT-PCR.

Results: Endothelial cell ICAM-1 immunostaining was similar in normal and inflamed or hemorrhagic decidua. In cultured DCs, optimal concentrations of IL-1ß, TNF, and thrombin elevated secreted IL-8 levels by 1083 ± 261-, 370 ± 77-, and 45 ± 15-fold, respectively (mean ± SEM; P < 0.05; n = 8). The effects were dose dependent and were unaffected by medroxyprogesterone acetate. Western blotting confirmed the ELISA results, and corresponding effects on IL-8 mRNA levels were observed.

Conclusions: Cytokine/thrombin-enhanced DC IL-8 expression interacts with constitutively expressed ICAM-1 in decidual endothelium to modulate neutrophil trafficking into hemorrhagic and inflamed first trimester decidua.

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