Mol. Hum. Reprod. Advance Access published online on April 22, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap030
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Thrombin and Interleukin-1β Decrease HOX Gene Expression in Human First Trimester Decidual Cells: Implications for Pregnancy Loss
1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine 2Department of Molecular, Cellular and Developmental Biology, Yale University
Corresponding Author: Hugh S. Taylor, Division of Reproductive Endocrinology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, Phone: 203-785-4005, Fax: 203-785-7819, Email: hugh.taylor{at}yale.edu
Bleeding or inflammation in early pregnancy may result in pregnancy loss or defective implantation. Their effect on HOX gene expression in first trimester decidua is unknown. Bleeding results in thrombin generation, while infection or inflammation results in production of cytokines typified by Interleukin-1β (IL-1β). First trimester decidual cells were pretreated with 17β estradiol (E2), medroxyprogesterone acetate (MPA) or both and subsequently treated with thrombin or IL-1 β. Affymatrix microarray analysis was used to assess the expression of all HOX genes and confirmed using real time RT-PCR. E2 or MPA treatment resulted in significant increases in HOXA10 and HOXA11. Subsequent treatment with thrombin resulted in diminished expression of HOXA10 and HOXA9. Treatment with IL-1 β resulted in decreased expression of HOXA1, 3, 9, 10, and 11. HOXA10 expression was reduced by 70% after thrombin treatment (p=0.018) and by 90% after IL-1 β treatment (p=0.004). HOXA11 mRNA expression was decreased by 88% after IL-1 β treatment (p<0.001), but not by thrombin treatment. Decidua was collected at the time of elective termination of pregnancy (n=10) or surgical treatment of spontaneous pregnancy loss(n=10). Real time PCR and western analysis demonstrated decreased HOXA10 and HOXA11 RNA and protein expression in the decidua of spontaneous pregnancy loss compared to that of viable pregnancies. In conclusion, multiple HOX genes are expressed in decidual cells and inhibited by thrombin and IL-1 β. Since HOXA10 and 11 are known to be necessary for successful pregnancy, these findings suggest a molecular mechanism by which bleeding or inflammation may affect pregnancy outcome.
Key Words: HOX/IL-1β/thrombin/decidual hemorrhage/pregnancy loss
Grant support: HD36887(HST), U54 HD052668(HST) and HL07004(CJL)
Submitted on November 24, 2006; resubmitted on March 26, 2009; accepted on April 2, 2009.