HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/2/E282    most recent 00328.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Kossintseva, I. Articles by Mitchell, B. F. Search for Related Content PubMed PubMed Citation Articles by Kossintseva, I. Articles by Mitchell, B. F.

Proinflammatory cytokines inhibit human placental 11-hydroxysteroid dehydrogenase type 2 activity through Ca²⁺ and cAMP pathways

Departments of ¹Obstetrics and Gynecology and ²Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada

Submitted 21 July 2005 ; accepted in final form 15 September 2005

Excessive fetal exposure to glucocorticoids has been implicated in the etiology of adult metabolic and cardiovascular disease. Placental 11-hydroxysteroid dehydrogenase type 2 (11-HSD2) may protect the fetus from excessive glucocorticoid exposure. Maternal stress may be accompanied by elevated levels of cortisol and increased proinflammatory cytokines [interleukin (IL)-1, IL-6, and tumor necrosis factor- (TNF-)]. We hypothesize that proinflammatory cytokines inhibit human placental 11-HSD activity. We incubated explant cultures of term human placental villi in the presence or absence of 10 ng/ml IL-1, IL-6, or TNF-, with or without agonists or antagonists of intracellular Ca²⁺ and adenylyl cyclase. Activity for 11-HSD2 was estimated using a radioisotope assay, and mRNA was measured using quantitative RT-PCR. All cytokines significantly (P 0.05) reduced 11-HSD2 activity (>75% suppression); maximal inhibition occurred within 2 h and was maintained for at least 24 h. The IL-1-induced inhibitory activity was attenuated using a Ca²⁺ channel blocker (nifedipine), an intracellular Ca²⁺ antagonist [8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate], or the adenylyl cyclase stimulant forskolin. Conversely, 11-HSD2 activity was diminished in the presence of the Ca²⁺ ionophore A-23187 or the adenylyl cyclase inhibitor SQ-22536. mRNA levels for 11-HSD2 were not changed by any of the treatments. Proinflammatory cytokines inhibit human placental 11-HSD2 activity through a mechanism that involves increased intracellular Ca²⁺ and inhibition of adenylyl cyclase. This could result in excessive fetal exposure to maternal cortisol. This mechanism might mediate part of the increased risk of metabolic and cardiovascular disease in adult offspring.

interleukin-1; interleukin-6; tumor necrosis factor-; cortisol; metabolic and vascular disease

This article has been cited by other articles:

				A. E. Michael and A. T. Papageorghiou Potential significance of physiological and pharmacological glucocorticoids in early pregnancy Hum. Reprod. Update, September 1, 2008; 14(5): 497 - 517. [Abstract] [Full Text] [PDF]