Lee JeHoon, Stanley Jone A, McCracken John A, Banu Sakhila K, Arosh Joe A
Reproductive Endocrinology and Cell Signaling Laboratory, Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas.
Department of Animal Science, University of Connecticut, Storrs, Connecticut.
Biol Reprod. 2014 Aug;91(2):46. doi: 10.1095/biolreprod.113.111872. Epub 2014 May 29.
In ruminants, prostaglandin F2 alpha (PGF2alpha) is synthesized and released in a pulsatile pattern from the endometrial luminal epithelial (LE) cells during the process of luteolysis. Interferon tau (IFNT) is a Type 1 IFN secreted by the trophoblast cells of the developing conceptus. IFNT acts locally on endometrial LE cells to inhibit pulsatile releases of PGF2alpha and thus establish an endocrine environment for recognition of pregnancy. Cell signaling pathways through which IFNT stimulates expression of multiple genes or proteins in endometrial LE are largely unknown. Results of the present investigation indicate that intrauterine administration of IFNT inhibits pulsatile release of PGF2alpha, while coadministration IFNT and ERK 1/2 inhibitor U0126 restores luteolytic PGF2alpha pulses in sheep. IFNT increases phosphorylation of ERK1/2 proteins and increases its interaction with PGT proteins in endometrial LE. Blockade of ERK1/2 pathways inhibits IFNT action, decreases pERK1/2 and PGT protein interactions, and re-establishes the spatial expression of the oxytocin receptor protein completely and the estrogen receptor protein partially without modulating the expression of interferon regulatory factor-2 (IRF-2) protein in endometrial LE. IFNT does not decrease expression of COX-2, PGDH, or PGT protein in endometrial LE. Our results provide important new insights into IFNT signaling and the molecular endocrine control of PGF2alpha release at the time of establishment of pregnancy in ruminants. This novel IFNT-ERK1/2 signaling module needs to be explored in future studies to understand molecular and cellular mechanisms of IFNT action in endometrial LE in ruminants.
在反刍动物中，在黄体溶解过程中，前列腺素F2α（PGF2α）以脉冲模式从子宫内膜腔上皮（LE）细胞合成并释放。干扰素τ（IFNT）是发育中的孕体滋养层细胞分泌的I型干扰素。IFNT作用于子宫内膜LE细胞，抑制PGF2α的脉冲式释放，从而建立一个用于识别妊娠的内分泌环境。IFNT刺激子宫内膜LE中多种基因或蛋白质表达的细胞信号通路在很大程度上尚不清楚。本研究结果表明，子宫内给予IFNT可抑制PGF2α的脉冲式释放，而同时给予IFNT和ERK 1/2抑制剂U0126可恢复绵羊黄体溶解期的PGF2α脉冲。IFNT增加子宫内膜LE中ERK1/2蛋白的磷酸化，并增加其与PGT蛋白的相互作用。阻断ERK1/2通路可抑制IFNT的作用，减少pERK1/2与PGT蛋白的相互作用，并完全重新建立催产素受体蛋白的空间表达以及部分重新建立雌激素受体蛋白的空间表达，而不调节子宫内膜LE中干扰素调节因子-2（IRF-2）蛋白的表达。IFNT不会降低子宫内膜LE中COX-2、PGDH或PGT蛋白的表达。我们的研究结果为反刍动物妊娠建立时IFNT信号传导以及PGF2α释放的分子内分泌控制提供了重要的新见解。这种新的IFNT-ERK1/2信号模块需要在未来的研究中进行探索，以了解反刍动物子宫内膜LE中IFNT作用的分子和细胞机制。
