DOI QR코드

DOI QR Code

Spatiotemporal expression and regulation of peptidase inhibitor 3 and secretory leukocyte protease inhibitor at the maternal-fetal interface in pigs

  • Soohyung Lee (Division of Biological Science and Technology, Yonsei University) ;
  • Inkyu Yoo (Division of Biological Science and Technology, Yonsei University) ;
  • Yugyeong Cheon (Division of Biological Science and Technology, Yonsei University) ;
  • Hakhyun Ka (Division of Biological Science and Technology, Yonsei University)
  • Received : 2022.11.01
  • Accepted : 2023.01.26
  • Published : 2023.07.01

Abstract

Objective: Two serine protease inhibitors, peptidase inhibitor 3 (PI3) and secretory leukocyte protease inhibitor (SLPI), play important roles in protease inhibition and antimicrobial activity, but their expression, regulation, and function at the maternal-fetal interface in pigs are not fully understood. Therefore, we determined the expression and regulation of PI3 and SLPI in the endometrium throughout the estrous cycle and at the maternal-fetal interface in pigs. Methods: Endometrial tissues during the estrous cycle and pregnancy, conceptus tissues during early pregnancy, and chorioallantoic tissues during mid to late pregnancy were obtained, and the expression of PI3 and SLPI was analyzed. The effects of the steroid hormones estradiol-17β (E2) and progesterone (P4) on the expression of PI3 and SLPI were determined in endometrial explant cultures. Results: PI3 and SLPI were expressed in the endometrium during the estrous cycle and pregnancy, with higher levels during mid to late pregnancy than during the estrous cycle and early pregnancy. Early-stage conceptuses and chorioallantoic tissues during mid to late pregnancy also expressed PI3 and SLPI. PI3 protein and SLPI mRNA were primarily localized to endometrial epithelia. In endometrial explant cultures, the expression of PI3 was induced by increasing doses of P4, and the expression of SLPI was induced by increasing doses of E2 and P4. Conclusion: These results suggest that the PI3 and SLPI expressed in the endometrium and conceptus tissues play an important role in antimicrobial activity for fetal protection against potential pathogens and in blocking protease actions to allow epitheliochorial placenta formation.

Keywords

Acknowledgement

This study was supported by a National Research Foundation grant funded by the Korean government (NRF-2019R1A2C1004670), Republic of Korea.

References

  1. Chaplin DD. 1. Overview of the human immune response. J Allergy Clin Immunol 2006;117:S430-5. https://doi.org/10.1016/j.jaci.2005.09.034 
  2. Gasteiger G, D'Osualdo A, Schubert DA, Weber A, Bruscia EM, Hartl D. Cellular innate immunity: an old game with new players. J Innate Immun 2017;9:111-25. https://doi.org/10.1159/000453397 
  3. Frew L, Stock SJ. Antimicrobial peptides and pregnancy. Reproduction 2011;141:725-35. https://doi.org/10.1530/REP-10-0537 
  4. Sallenave JM. Secretory leukocyte protease inhibitor and elafin/trappin-2: versatile mucosal antimicrobials and regulators of immunity. Am J Respir Cell Mol Biol 2010;42:635-43. https://doi.org/10.1165/rcmb.2010-0095RT 
  5. Moreau T, Baranger K, Dade S, Dallet-Choisy S, Guyot N, Zani M. Multifaceted roles of human elafin and secretory leukocyte proteinase inhibitor (SLPI), two serine protease inhibitors of the chelonianin family. Biochimie 2008;90:284-95. https://doi.org/10.1016/j.biochi.2007.09.007 
  6. Pham CT. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 2006;6:541-50. https://doi.org/10.1038/nri1841 
  7. Pfundt R, Wingens M, Bergers M, Zweers M, Frenken M, Schalkwijk J. TNF-alpha and serum induce SKALP/elafin gene expression in human keratinocytes by a p38 MAP kinase-dependent pathway. Arch Dermatol Res 2000;292:180-7. https://doi.org/10.1007/s004030050475 
  8. Reid PT, Marsden ME, Cunningham GA, Haslett C, Sallenave JM. Human neutrophil elastase regulates the expression and secretion of elafin (elastase-specific inhibitor) in type II alveolar epithelial cells. FEBS Lett 1999;457:33-7. https://doi.org/10.1016/s0014-5793(99)01004-2 
  9. Amjadi F, Salehi E, Mehdizadeh M, Aflatoonian R. Role of the innate immunity in female reproductive tract. Adv Biomed Res 2014;3:1. https://doi.org/10.4103/2277-9175.124626 
  10. King AE, Critchley HO, Kelly RW. Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role. Mol Hum Reprod 2000;6:191-6. https://doi.org/10.1093/molehr/6.2.191 
  11. Reed KL, Blaeser LL, Dantzer V, Green ML, Simmen RCM. Control of secretory leukocyte protease inhibitor gene expression in the porcine periimplantation endometrium: a case of maternal-embryo communication. Biol Reprod 1998;58:448-57. https://doi.org/10.1095/biolreprod58.2.448 
  12. Farmer SJ, Fliss AE, Simmen RC. Complementary DNA cloning and regulation of expression of the messenger RNA encoding a pregnancy-associated porcine uterine protein related to human antileukoproteinase. Mol Endocrinol 1990;4:1095-104. https://doi.org/10.1210/mend-4-8-1095 
  13. King AE, Critchley HO, Kelly RW. Innate immune defences in the human endometrium. Reprod Biol Endocrinol 2003;1:116. https://doi.org/10.1186/1477-7827-1-116 
  14. King AE, Morgan K, Sallenave JM, Kelly RW. Differential regulation of secretory leukocyte protease inhibitor and elafin by progesterone. Biochem Biophys Res Commun 2003;310:594-9. https://doi.org/10.1016/j.bbrc.2003.08.151 
  15. King AE, Critchley HO, Sallenave JM, Kelly RW. Elafin in human endometrium: an antiprotease and antimicrobial molecule expressed during menstruation. J Clin Endocrinol Metab 2003;88:4426-31. https://doi.org/10.1210/jc.2003-030239 
  16. Oestrup O, Hall V, Petkov SG, Wolf XA, Hyldig S, Hyttel P. From zygote to implantation: morphological and molecular dynamics during embryo development in the pig. Reprod Domest Anim 2009;44(Suppl 3):39-49. https://doi.org/10.1111/j.1439-0531.2009.01482.x 
  17. Yoo I, Jung W, Lee S, Cheon Y, Ka H. Inhibitors of apoptosis: expression and regulation in the endometrium during the estrous cycle and at the maternal-conceptus interface during pregnancy in pigs. Anim Biosci 2022;35:533-43. https://doi.org/10.5713/ab.21.0307 
  18. Ka H, Seo H, Choi Y, Yoo I, Han J. Endometrial response to conceptus-derived estrogen and interleukin-1beta at the time of implantation in pigs. J Anim Sci Biotechnol 2018;9:44. https://doi.org/10.1186/s40104-018-0259-8 
  19. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001;25:402-8. https://doi.org/10.1006/meth.2001.1262 
  20. Williams SE, Brown TI, Roghanian A, Sallenave JM. SLPI and elafin: one glove, many fingers. Clin Sci (Lond) 2006;110:21-35. https://doi.org/10.1042/CS20050115 
  21. Ibrahim M, Peter S, Gartner MA, et al. Increased mRNA expression of selected antimicrobial peptides around ovulation and during inflammatory processes in the bovine endometrium postpartum. Theriogenology 2016;86:2040-53. https://doi.org/10.1016/j.theriogenology.2016.06.022 
  22. Lee S, Yoo I, Han J, Ka H. Antimicrobial peptides cathelicidin, PMAP23, and PMAP37: Expression in the endometrium throughout the estrous cycle and at the maternal-conceptus interface during pregnancy and regulation by steroid hormones and calcitriol in pigs. Theriogenology 2021;160:1-9. https://doi.org/10.1016/j.theriogenology.2020.10.034
  23. Lee S, Jang H, Yoo I, Han J, Jung W, Ka H. Unique epithelial expression of S100A calcium binding protein A7A in the endometrium at conceptus implantation in pigs. Asian-Australas J Anim Sci 2019;32:1355-62. https://doi.org/10.5713/ajas.18.0920 
  24. Jang H, Lee S, Yoo I, et al. Calcium-binding proteins S100A8, S100A9, and S100A12: expression and regulation at the maternal-conceptus interface in pigs. Biol Reprod 2022;106:1098-111. https://doi.org/10.1093/biolre/ioac039 
  25. Ramuta TZ, Sket T, Starcic Erjavec M, Kreft ME. Antimicrobial activity of human fetal membranes: from biological function to clinical use. Front Bioeng Biotechnol 2021;9:691522. https://doi.org/10.3389/fbioe.2021.691522 
  26. Simmen RC, Michel FJ, Fliss AE, Smith LC, Fliss MF. Ontogeny, immunocytochemical localization, and biochemical properties of the pregnancy-associated uterine elastase/cathepsin-G protease inhibitor, antileukoproteinase (ALP): monospecific antibodies to a synthetic peptide recognize native ALP. Endocrinology 1992;130:1957-65. https://doi.org/10.1210/endo.130.4.1547723 
  27. Fahey JV, Wright JA, Shen L, et al. Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture. Mucosal Immunol 2008;1:317-25. https://doi.org/10.1038/mi.2008.20 
  28. Reed KL, Badinga L, Davis DL, Chung TE, Simmen RCM. Porcine endometrial glandular epithelial cells in vitro: transcriptional activities of the pregnancy-associated genes encoding antileukoproteinase and uteroferrin. Biol Reprod 1996;55:469-77. https://doi.org/10.1095/biolreprod55.2.469 
  29. Bazer FW, Johnson GA. Pig blastocyst-uterine interactions. Differentiation 2014;87:52-65. https://doi.org/10.1016/j.diff.2013.11.005 
  30. Yoo I, Kim M, Han J, et al. Pro-inflammatory cytokines and their receptors: expression and regulation in the uterine endometrium during the estrous cycle in pigs. J Embryo Trans 2016;31:323-33. https://doi.org/10.12750/JET.2016.31.4.323 
  31. Lala PK, Graham CH. Mechanisms of trophoblast invasiveness and their control: the role of proteases and protease inhibitors. Cancer Metastasis Rev 1990;9:369-79. https://doi.org/10.1007/BF00049525 
  32. Dantzer V. Electron microscopy of the initial stages of placentation in the pig. Anat Embryol (Berl) 1985;172:281-93. https://doi.org/10.1007/BF00318976 
  33. Badinga L, Michel FJ, Fields MJ, Sharp DC, Simmen RCM. Pregnancy-associated endometrial expression of antileukoproteinase gene is correlated with epitheliochorial placentation. Mol Reprod Dev 1994;38:357-63. https://doi.org/10.1002/mrd.1080380402