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Thrombin and Interleukin-1ß Regulate HOXA10 Expression in Human Term Decidual Cells: Implications for Preterm Labor

Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Hugh S. Taylor, M.D., Associate Professor, Division of Reproductive Endocrinology and Fertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520. E-mail: hugh.taylor{at}yale.edu.

Context: Preterm delivery is commonly caused by intraamniotic infection with expression of proinflammatory cytokines (IL-1ß) or by abruption resulting in generation of decidual thrombin. Although human parturition is not preceded by overt progesterone withdrawal, progesterone resistance likely leads to labor. The uteri of Hoxa10(–/–) mice demonstrate progesterone resistance; several genes, including prostaglandin receptors, are inappropriately regulated in response to progesterone.

Objective: We hypothesized that IL-1ß or thrombin would decrease HOXA10 expression, contributing to the progestin-resistant environment. We analyzed expression of HOX genes and their regulation by IL-1ß or thrombin in decidual cells.

Design and Setting: We conducted an in vitro experiment at an academic medical center.

Intervention: Term decidual cells were treated with estradiol (E₂) or E₂ plus medroxyprogesterone acetate followed by addition of thrombin or IL-1ß.

Main Outcome Measure: HOX mRNA was evaluated by microarray and confirmed by quantitative RT-PCR. Protein expression was detected using immunohistochemistry and Western analysis.

Results: HOXA9, HOXA10, and HOXA11 were expressed in decidual cells and regulated by IL-1ß and thrombin. HOXA10 was further analyzed because of its association with progesterone responsiveness. After E₂ treatment, IL-1ß and thrombin decreased HOXA10 mRNA by 94 and 81%, respectively. After E₂ plus medroxyprogesterone acetate treatment, IL-1ß and thrombin resulted in an 86 and 72% decrease in HOXA10 mRNA, respectively. A similar decrease was noted in HOXA10 protein expression.

Conclusion: The expression of HOXA10 protein at term indicates that it may have a role in maintaining decidual cell phenotype and pregnancy. The dramatic decrease of HOXA10 in response to IL-1ß or thrombin may contribute to progestin resistance in preterm labor, mimicking progesterone resistance seen in Hoxa10(–/–) mice.

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