Published online before print May 8, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070629

Accepted for publication February 22, 2008.

Article

Preeclampsia-Related Inflammatory Cytokines Regulate Interleukin-6 Expression in Human Decidual Cells

Charles J. Lockwood^*, Chih-Feng Yen, Murat Basar, Umit A. Kayisli^*, Maritza Martel, Irina Buhimschi^*, Catalin Buhimschi^*, S. Joseph Huang^*, Graciela Krikun^*, and Frederick Schatz^*@

From the Departments of Obstetrics, Gynecology, and Reproductive Sciences,* and Pathology, Yale University School of Medicine, New Haven, Connecticut; the Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Tao-Yuan, Taiwan; and the Department of Histology and Embryology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

^@ To whom correspondence should be addressed. E-mail: frederick.schatz{at}yale.edu.

	Abstract

Preeclampsia, a common pregnancy disorder associated with an increase in systemic inflammation, is the leading cause of maternal and fetal morbidity and mortality throughout the world. It is associated with shallow extravillous trophoblast invasion of the decidua, leading to uteroplacental blood flow that is inadequate for the developing fetal-placental unit. In preeclamptic women, interleukin-6 (IL-6) levels in plasma, but not placenta, are elevated, prompting evaluation of the decidua as a potential source of this excess, circulating IL-6. The current study found significantly higher immunohistochemical staining for IL-6 in decidual cells from preeclamptic versus preterm, gestational age-matched control placentas. Pro-inflammatory cytokines associated with the genesis of preeclampsia (i.e., tumor necrosis factor- and interleukin-1) enhanced IL-6 mRNA levels and increased secreted IL-6 levels in first trimester leukocyte-free decidual cell incubations, as measured by real time quantitative RT-PCR, ELISA, and Western blotting. Therefore, decidual cell-derived IL-6 may contribute to excess circulating IL-6 levels that can promote both endothelial cell dysfunction (and subsequent vascular dysfunction) and the pathogenesis of preeclampsia whereas locally elevated IL-6 levels may contribute to an excess of decidual macrophages implicated in shallow extravillous trophoblast invasion of the decidua.