A novel pathway involving progesterone receptor, 12/15-lipoxygenase-derived eicosanoids, and peroxisome proliferator-activated receptor gamma regulates implantation in mice.
The 12/15-lipoxygenases (12/15-LOX) catalyze the stereo-specific oxygenation of arachidonic and linoleic acids into a complex series of signaling molecules, including the hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs). Our previous studies, using high density oligonucleotide microarrays, suggested a novel link between progesterone receptor (PR) signaling and 12/15-LOX-mediated fatty acid metabolism in preimplantation mouse uterus. In this paper, using PR knockout mice, we established that the transcripts encoding leukocyte-12/15-LOX (L-12/15-LOX) and epidermal-12/15-LOX (E-12/15-LOX) are indeed downstream targets of regulation by PR in the uterine surface epithelium. Maximal induction of both L- and E-12/15-LOX on the day of implantation resulted in a marked increase in the uterine levels of the eicosanoids, 12-HETE, 15-HETE, and 13-HODE. Mice with null mutation in L-12/15-LOX had significantly reduced uterine levels of arachidonic acid metabolites and exhibited a partial impairment in implantation. Complete blockade of uterine 12/15-LOX activity by a specific inhibitor led to greater than 80% reduction in a number of implantation sites relative to untreated controls. Cell-based assays indicated that 12-HETE, 15-HETE, and 13-HODE function as activating ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), suggesting that this nuclear receptor could be a downstream target of 12/15-LOX-derived metabolites in the preimplantation uterus. Consistent with this hypothesis, administration of rosiglitazone, a potent PPARgamma-selective agonist, efficiently reversed inhibition of implantation by the 12/15-LOX-specific inhibitor. Rosiglitazone also induced a number of potential target genes of 12/15-LOX-derived metabolites in the pregnant uterus, indicating their regulation by PPARgamma. Collectively, our results uncovered a novel signaling pathway in which progesterone-induced synthesis of the 12/15-LOX-derived lipid mediators activates PPARgamma and its downstream gene networks, which in turn function as critical regulators of implantation in the mouse.
Li
Quanxi
Q
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Cheon
Yong-Pil
YP
Kannan
Athilaxmi
A
Shanker
Sreenath
S
Bagchi
Indrani C
IC
Bagchi
Milan K
MK
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D010064:Embryo Implantation; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D015777:Eicosanoids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011980:Receptors, Progesterone; D014157:Transcription Factors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase