Thrombin and interleukin-1beta regulate HOXA10 expression in human term decidual cells: implications for preterm labor.
BACKGROUND
Preterm delivery is commonly caused by intraamniotic infection with expression of proinflammatory cytokines (IL-1beta) 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-1beta or thrombin would decrease HOXA10 expression, contributing to the progestin-resistant environment. We analyzed expression of HOX genes and their regulation by IL-1beta or thrombin in decidual cells.


METHODS
We conducted an in vitro experiment at an academic medical center.


METHODS
Term decidual cells were treated with estradiol (E(2)) or E(2) plus medroxyprogesterone acetate followed by addition of thrombin or IL-1beta.


METHODS
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-1beta and thrombin. HOXA10 was further analyzed because of its association with progesterone responsiveness. After E(2) treatment, IL-1beta and thrombin decreased HOXA10 mRNA by 94 and 81%, respectively. After E(2) plus medroxyprogesterone acetate treatment, IL-1beta and thrombin resulted in an 86 and 72% decrease in HOXA10 mRNA, respectively. A similar decrease was noted in HOXA10 protein expression.


CONCLUSIONS
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-1beta or thrombin may contribute to progestin resistance in preterm labor, mimicking progesterone resistance seen in Hoxa10(-/-) mice.
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, USA.
Jennifer L
JL
Sarno
Frederick
F
Schatz
Charles J
CJ
Lockwood
S-T Joseph
ST
Huang
Hugh S
HS
Taylor
D002478:Cells, Cultured; D003656:Decidua / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007752:Obstetric Labor, Premature / Q000209:etiology*; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*
D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D007375:Interleukin-1; C092119:Hoxa10 protein, mouse; D011374:Progesterone; D013917:Thrombin