Can medroxyprogesterone acetate alter Toll-like receptor expression in a mouse model of intrauterine inflammation?
OBJECTIVE
Activation of the innate immune receptors, Toll-like receptors 2 and 4, are critical for a host inflammatory response to both Gram-positive and Gram-negative organisms. These receptors can initiate and modulate the inflammatory response. Differential regulation of Toll-like receptors may be one of the mechanisms by which intrauterine inflammation signals parturition. Likewise, progestational agents may have the ability to modify this effect. These studies were performed to elucidate the effect of intrauterine inflammation and medroxyprogesterone acetate on Toll-like receptor expression in the uterus, cervix, and placenta in a mouse model of intrauterine inflammation.


METHODS
On day 15 of gestation, CD-1 mice were randomized to pretreatment with medroxyprogesterone acetate or vehicle before intrauterine infusion with lipopolysaccharide or sterile saline solution. Six hours after intrauterine infusion, uterine, cervical, and placental tissues were harvested. RNA and protein were extracted. Quantitative polymerase chain reaction was performed for Toll-like receptor 2 and 4 messenger RNA. Western blot analysis was performed with Toll-like receptor 4-specific antibodies.


RESULTS
Intrauterine inflammation up-regulated Toll-like receptor 2 and 4 messenger RNA in uterus, cervix, and placenta. Pretreatment with medroxyprogesterone acetate decreased the lipopolysaccharide-induced up-regulation of Toll-like receptor 2 and 4 messenger RNA in the cervix and placenta. Medroxyprogesterone acetate treatment, in the presence of lipopolysaccharide, was unable to prevent the lipopolysaccharide-induced increase in Toll-like receptor 4 messenger RNA and protein in the uterus. Medroxyprogesterone acetate treatment alone in pregnant mice significantly increased Toll-like receptor 4 messenger RNA expression in the uterus.


CONCLUSIONS
Intrauterine inflammation has a differential effect on Toll-like receptor 2 and 4 expression. The observed up-regulation of Toll-like receptor 2 in the uterus in response to intrauterine lipopolysaccharide may be a mechanism to augment the inflammatory response and may serve to promote parturition in the setting of inflammation. Consequently, the ability of medroxyprogesterone acetate to suppress lipopolysaccharide-induced up-regulation of Toll-like receptor 2 messenger RNA may be one of the mechanisms by which progestins are able to decrease preterm birth.
Elovitz
Michal A
MA
Department of Obstetrics and Gynecology, Center for Research in Reproduction and Women's Health, University of Pennsylvania, Philadelphia, PA, USA. melovitz@obgyn.upenn.edu
Mrinalini
Conjeevaram
C
D000818:Animals; D015153:Blotting, Western; D002584:Cervix Uteri / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D047928:Premature Birth / Q000378:metabolism* / Q000517:prevention & control; D011897:Random Allocation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014599:Uterus / Q000378:metabolism* / Q000473:pathology
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D017258:Medroxyprogesterone Acetate