Urocortins exhibit differential effects on PGE2 and PGF output via CRHR2 in human myometrium

in Reproduction
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  • 1 Department of Gynecology and Obstetrics and Research Center for Molecular Metabolomics, Xiangya Hospital Central South University, Changsha, China
  • 2 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
  • 3 Department of Physiology, Navy Medical University, Shanghai, China
  • 4 Medical School of Shanghai University, Shanghai, China
  • 5 Department of Gynecology and Obstetrics, Changhai Hospital, Shanghai, China

Correspondence should be addressed to X Ni; Email: xinni2018@csu.edu.cn
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Urocortins (UCNs), belonging to corticotropin-releasing hormone (CRH) family, exert their function via CRH receptor type 1 (CRHR1) and 2 (CRHR2). Our previous studies have demonstrated that CRH acts on CRHR1 to potentiate prostaglandins (PGs) output induced by inflammatory stimuli in myometrial cells. In the present study, we sought to investigate the effects of UCNs on prostaglandin (PG) output via CRHR2 in cultured human uterine smooth muscle cells (HUSMCs) from pregnant women at term. We found that UCN and UCN 3 treatment promoted PGE2 and PGF2α secretion in a dose-dependent manner. In contrast, UCN2 dose-dependently inhibited PGE2 and PGF2α secretion. Their effects were reversed by CRHR2 antagonist and CRHR2 siRNA. Mechanically, we showed that UCN and UCN3 suppressed cAMP production and led to Gi activation while UCN2 stimulated cAMP production and activated Gs signaling. Further, UCN and UCN3 but not UCN2 activated NF-κB and MAPK signaling pathways through Gi signaling. UCN and UCN3 stimulation of PGs secretion were dependent on Gi/adenylyl cyclase (AC)/cAMP, NF-κB and MAPK signaling pathways. UCN2 suppression of PGs output was through Gs/AC/cAMP signaling pathways. Our data suggest that UCN, UCN2 and UCN3 can finely regulate PGs secretion via CRHR2, which facilitates the functional status of the uterus during pregnancy.

 

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  • Deussing JM & Chen A 2018 The corticotropin-releasing factor family: physiology of the stress response. Physiological Reviews 98 22252286. (https://doi.org/10.1152/physrev.00042.2017)

    • Search Google Scholar
    • Export Citation
  • Fukushima N, Kohno M, Kato T, Kawamoto S, Okuda K, Misu Y & Ueda H 1998 Melittin, a metabostatic peptide inhibiting Gs activity. Peptides 19 81181 9. (https://doi.org/10.1016/s0196-9781(9800027-8)

    • Search Google Scholar
    • Export Citation
  • Gao L, He P, Sha J, Liu C, Dai L, Hui N & Ni X 2007 Corticotropin-releasing hormone receptor type 1 and type 2 mediate differential effects on 15-hydroxy prostaglandin dehydrogenase expression in cultured human chorion trophoblasts. Endocrinology 148 364536 54 (https://doi.org/10.1210/en.2006-1212)

    • Search Google Scholar
    • Export Citation
  • Gao L, Lu C, Xu C, Tao Y, Cong B & Ni X 2008 Differential regulation of prostaglandin production mediated by corticotropin-releasing hormone receptor type 1 and type 2 in cultured human placental trophoblasts. Endocrinology 149 286628 76. (https://doi.org/10.1210/en.2007-1377)

    • Search Google Scholar
    • Export Citation
  • Grammatopoulos DK 2007 The role of CRH receptors and their agonists in myometrial contractility and quiescence during pregnancy and labour. Frontiers in Bioscience 12 5615 71. (https://doi.org/10.2741/2082)

    • Search Google Scholar
    • Export Citation
  • Grammatopoulos DK, Randeva HS, Levine MA, Katsanou ES & Hillhouse EW 2000 Urocortin, but not corticotropin-releasing hormone (CRH), activates the mitogen-activated protein kinase signal transduction pathway in human pregnant myometrium: an effect mediated via R1alpha and R2beta CRH receptor subtypes and stimulation of Gq-proteins. Molecular Endocrinology 14 207620 91. (https://doi.org/10.1210/mend.14.12.0574)

    • Search Google Scholar
    • Export Citation
  • Guild SB 2001 Effects of phospholipase A(2) activating peptides upon GTP-binding protein-evoked adrenocorticotrophin secretion. European Journal of Pharmacology 424 1631 71. (https://doi.org/10.1016/s0014-2999(0101149-9)

    • Search Google Scholar
    • Export Citation
  • Imperatore A, Li W, Petraglia F & Challis JR 2009 Urocortin 2 stimulates estradiol secretion from cultured human placental cells: an effect mediated by the type 2 corticotrophin-releasing hormone (CRH) receptor. Reproductive Sciences 16 55155 8. (https://doi.org/10.1177/1933719109332830)

    • Search Google Scholar
    • Export Citation
  • Jin D, He P, You X, Zhu X, Dai L, He Q, Liu C, Hui N, Sha J & Ni X 2007 Expression of corticotropin-releasing hormone receptor type 1 and type 2 in human pregnant myometrium. Reproductive Sciences 14 5685 77. (https://doi.org/10.1177/1933719107307821)

    • Search Google Scholar
    • Export Citation
  • Karteris E, Grammatopoulos DK, Randeva HS & Hillhouse EW 2001 The role of corticotropin-releasing hormone receptors in placenta and fetal membranes during human pregnancy. Molecular Genetics and Metabolism 72 2872 96. (https://doi.org/10.1006/mgme.2001.3159)

    • Search Google Scholar
    • Export Citation
  • Karteris E, Hillhouse EW & Grammatopoulos D 2004 Urocortin II is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation: potential role of the type-2 corticotropin-releasing hormone receptor in the control of myometrial contractility. Endocrinology 145 890900. (https://doi.org/10.1210/en.2003-1210)

    • Search Google Scholar
    • Export Citation
  • Makrigiannakis A, Vrekoussis T, Zoumakis E, Navrozoglou I & Kalantaridou SN 2018 CRH receptors in human reproduction. Current Molecular Pharmacology 11 8187. (https://doi.org/10.2174/1874467210666170224094146)

    • Search Google Scholar
    • Export Citation
  • McLean M & Smith R 2001 Corticotrophin-releasing hormone and human parturition. Reproduction 121 493501. (https://doi.org/10.1530/rep.0.1210493)

    • Search Google Scholar
    • Export Citation
  • Novembri R, Carrarelli P, Toti P, Rocha AL, Borges LE, Reis FM, Piomboni P, Florio P & Petraglia F 2011a Urocortin 2 and urocortin 3 in endometriosis: evidence for a possible role in inflammatory response. Molecular Human Reproduction 17 5875 93. (https://doi.org/10.1093/molehr/gar020)

    • Search Google Scholar
    • Export Citation
  • Novembri R, Torricelli M, Bloise E, Conti N, Galeazzi LR, Severi FM & Petraglia F 2011b Effects of urocortin 2 and urocortin 3 on IL-10 and TNF-alpha expression and secretion from human trophoblast explants. Placenta 32 9699 74. (https://doi.org/10.1016/j.placenta.2011.09.013)

    • Search Google Scholar
    • Export Citation
  • Petraglia F, Florio P, Benedetto C, Marozio L, Di Blasio AM, Ticconi C, Piccione E, Luisi S, Genazzani AR & Vale W 1999 Urocortin stimulates placental adrenocorticotropin and prostaglandin release and myometrial contractility in vitro. Journal of Clinical Endocrinology and Metabolism 84 1420142 3. (https://doi.org/10.1210/jcem.84.4.5585)

    • Search Google Scholar
    • Export Citation
  • Petraglia F, Imperatore A & Challis JR 2010 Neuroendocrine mechanisms in pregnancy and parturition. Endocrine Reviews 31 783816. (https://doi.org/10.1210/er.2009-0019)

    • Search Google Scholar
    • Export Citation
  • Smith R 2007 Parturition. New England Journal of Medicine 356 271283. (https://doi.org/10.1056/NEJMra061360)

  • Vannuccini S, Bocchi C, Severi FM, Challis JR & Petraglia F 2016 Endocrinology of human parturition. Annales d’Endocrinologie 77 1051 1 3. (https://doi.org/10.1016/j.ando.2016.04.025)

    • Search Google Scholar
    • Export Citation
  • Vitale SG, Laganà AS, Rapisarda AM, Scarale MG, Corrado F, Cignini P, Butticè S & Rossetti D 2016 Role of urocortin in pregnancy: an update and future perspectives. World Journal of Clinical Cases 4 1651 71. (https://doi.org/10.12998/wjcc.v4.i7.165)

    • Search Google Scholar
    • Export Citation
  • Voltolini C, Battersby S, Novembri R, Torricelli M, Severi FM, Petraglia F & Norman JE 2015 Urocortin 2 role in placental and myometrial inflammatory mechanisms at parturition. Endocrinology 156 67067 9. (https://doi.org/10.1210/en.2014-1432)

    • Search Google Scholar
    • Export Citation
  • Wang W, Qiao Y & Li Z 2018 New insights into modes of GPCR activation. Trends in Pharmacological Sciences 39 367386. (https://doi.org/10.1016/j.tips.2018.01.001)

    • Search Google Scholar
    • Export Citation
  • Wang X, Yuan L, Huang J, Zhang TL & Wang K 2008 Lanthanum enhances in vitro osteoblast differentiation via pertussis toxin-sensitive Gi protein and ERK signaling pathway. Journal of Cellular Biochemistry 105 13071 31 5. (https://doi.org/10.1002/jcb.21932)

    • Search Google Scholar
    • Export Citation
  • Wetzka B, Sehringer B, Schäfer WR, Biller S, Hör C, Benedek E, Deppert WR & Zahradnik HP 2003 Expression patterns of CRH, CRH receptors, and CRH binding protein in human gestational tissue at term. Experimental and Clinical Endocrinology and Diabetes 111 1541 61. (https://doi.org/10.1055/s-2003-39778)

    • Search Google Scholar
    • Export Citation
  • Xu C, Gao L, You X, Dai L, Li Y, Gu H, Slater DM, Olson DM & Ni X 2011 CRH acts on CRH-R1 and -R2 to differentially modulate the expression of large-conductance calcium-activated potassium channels in human pregnant myometrium. Endocrinology 152 440644 17. (https://doi.org/10.1210/en.2011-0262)

    • Search Google Scholar
    • Export Citation
  • Xu C, You X, Liu W, Sun Q, Ding X, Huang Y & Ni X 2015 Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways. Reproduction 149 1391 46. (https://doi.org/10.1530/REP-14-0479)

    • Search Google Scholar
    • Export Citation
  • You X, Gao L, Liu J, Xu C, Liu C, Li Y, Hui N, Gu H & Ni X 2012 CRH activation of different signaling pathways results in differential calcium signaling in human pregnant myometrium before and during labor. Journal of Clinical Endocrinology and Metabolism 97 E1851E18 61. (https://doi.org/10.1210/jc.2011-3383)

    • Search Google Scholar
    • Export Citation
  • You X, Liu J, Xu C, Liu W, Zhu X, Li Y, Sun Q, Gu H & Ni X 2014 Corticotropin-releasing hormone (CRH) promotes inflammation in human pregnant myometrium: the evidence of CRH initiating parturition? Journal of Clinical Endocrinology and Metabolism 99 E199E 208. (https://doi.org/10.1210/jc.2013-3366)

    • Search Google Scholar
    • Export Citation
  • Zhang LM, Wang YK, Hui N, Sha JY, Chen X, Guan R, Dai L, Gao L, Yuan WJ & Ni X 2008 Corticotropin-releasing hormone acts on CRH-R1 to inhibit the spontaneous contractility of non-labouring human myometrium at term. Life Sciences 83 620624. (https://doi.org/10.1016/j.lfs.2008.08.014)

    • Search Google Scholar
    • Export Citation