Progesterone and cAMP synergize to inhibit responsiveness of myometrial cells to pro-inflammatory/pro-labor stimuli
Progesterone and cAMP synergize to inhibit responsiveness of myometrial cells to pro-inflammatory/pro-labor stimuli
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DOI：
10.1016/j.mce.2018.08.005
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发表时间：
2019-01-05
影响因子：
4.1
通讯作者：
Mesiano, Sam
中科院分区：
文献类型：
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作者：
Amini, Peyvand;Wilson, Rachel;Mesiano, Sam
孕激素（P4）通过P4受体（PR）亚型PR-A和PR-B发挥作用，部分通过抑制子宫肌层细胞对促分娩炎症刺激的反应，促进妊娠大部分时间的子宫静止。这种抗炎作用被PR-A在丝氨酸-344和-345处的磷酸化（pSer（344/345）-PRA）抑制。环磷酸腺苷（cAMP）信号通路的激活也促进子宫静止和子宫肌层松弛。本研究检测了P4/PR和cAMP信号传导之间的相互作用，以发挥抗炎作用并控制子宫肌层细胞中pSer（344/345）-PRA的产生。在hTERT-HMA/B永生化人子宫肌层细胞系中，P4抑制了对白介素（IL）-1 β和毛喉素的反应（增加cAMP），8-Br-cAMP以浓度依赖性和协同方式增加了这种效应，这种效应是通过激活蛋白激酶A（PKA）介导的。Forskolin还抑制pSer（344/345）-PRA的产生和关键收缩相关基因的表达。pSer（344/345）-PRA的产生由应激活化蛋白激酶/c-Jun氨基末端激酶（SAPK/JNK）催化。毛喉素抑制pSer（344/345）-PRA的产生，部分是通过增加双特异性蛋白磷酸酶1（DUSP 1）的表达，DUSP 1是一种使丝裂原活化蛋白激酶（MAPK）（包括SAPK/JNK）失活的磷酸酶。P4/PR和forskolin增加DUSP 1表达。这些数据表明，P4/PR通过与子宫肌层细胞中cAMP/PKA信号转导的串扰和协同作用促进子宫静止，其中涉及DUSP 1介导的SAPK/JNK活化的抑制。
Progesterone (P4) acing through the P4 receptor (PR) isoforms, PR-A and PR-B, promotes uterine quiescence for most of pregnancy, in part, by inhibiting the response of myometrial cells to pro-labor inflammatory stimuli. This anti-inflammatory effect is inhibited by phosphorylation of PR-A at serine-344 and -345 (pSer(344/345)-PRA). Activation of the cyclic adenosine monophosphate (cAMP) signaling pathway also promotes uterine quiescence and myometrial relaxation. This study examined the cross-talk between P4/PR and cAMP signaling to exert anti-inflammatory actions and control pSer(344/345)-PRA generation in myometrial cells. In the hTERT-HMA/B immortalized human myometrial cell line P4 inhibited responsiveness to interleukin (IL)-1 beta and forskolin (increases cAMP) and 8-Br-cAMP increased this effect in a concentration-dependent and synergistic manner that was mediated by activation of protein kinase A (PKA). Forskolin also inhibited the generation of pSer(344/345)-PRA and expression of key contraction-associated genes. Generation of pSer(344/345)-PRA was catalyzed by stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Forskolin inhibited pSer(344/345)-PRA generation, in part, by increasing the expression of dual specificity protein phosphatase 1 (DUSP1), a phosphatase that inactivates mitogen-activated protein kinases (MAPKs) including SAPK/JNK. P4/PR and forskolin increased DUSP1 expression. The data suggest that P4/PR promotes uterine quiescence via cross-talk and synergy with cAMP/PKA signaling in myometrial cells that involves DUSP1-mediated inhibition of SAPK/JNK activation.