Putative Functions of Tissue Kallikrein-related Peptidases in Vaginal Fluid

Overview

Journal Nat Rev Urol

Specialty Urology

Date 2016 Sep 8

PMID 27603220

Citations 15

Authors

Carla M J Muytjens

Stella K Vasiliou

Katerina Oikonomopoulou

Ioannis Prassas

Eleftherios P Diamandis

Affiliations

Soon will be listed here.

Abstract

Cervical-vaginal fluid (CVF) is a complex biological fluid that hydrates the mucosa of the lower female reproductive system. In-depth proteomic and biochemical studies on CVF have revealed that it contains large amounts of endogenous proteases and protease inhibitors, including an abundance of several members of the tissue kallikrein-related peptidase (KLK) family. Despite their ubiquitous presence in human tissues and fluids, KLK expression levels vary considerably, with maximum expression observed in reproduction-related tissues and fluids. The roles of KLKs in the lower female reproductive system are not fully understood. The activation of KLKs in CVF is dependent on pH and various modes of KLK regulation in the vagina exist. KLKs have been postulated to have roles in physiological functions related to antimicrobial processes, vaginal and cervical epithelial desquamation, sperm transport, and the processing of fetal membranes as observed in preterm premature rupture of membranes. Increased understanding of the functional roles of KLKs in the lower female reproductive system could lead to new diagnostic and therapeutic modalities for conditions such as vaginal infections and vaginal atrophy.

Citing Articles

Exploring the therapeutic effect of melatonin targeting common biomarkers in testicular germ cell tumor, prostate adenocarcinoma, and male infertility: an integrated biology approach.

Wanjari U, Gopalakrishnan A Mamm Genome. 2025; .

PMID: 40056207 DOI: 10.1007/s00335-025-10119-x.

The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids.

Lachance G, Robitaille K, Laaraj J, Gevariya N, Varin T, Feldiorean A Nat Commun. 2024; 15(1):3431.

PMID: 38654015 PMC: 11039720. DOI: 10.1038/s41467-024-45332-w.

mTORC1 signaling pathway integrates estrogen and growth factor to coordinate vaginal epithelial cells proliferation and differentiation.

Wan S, Sun Y, Fu J, Song H, Xiao Z, Yang Q Cell Death Dis. 2022; 13(10):862.

PMID: 36220823 PMC: 9553898. DOI: 10.1038/s41419-022-05293-8.

Altered microbial biogeography in an innate model of colitis.

Boger-May A, Reed T, LaTorre D, Ruley-Haase K, Hoffman H, English L Gut Microbes. 2022; 14(1):2123677.

PMID: 36162004 PMC: 9519015. DOI: 10.1080/19490976.2022.2123677.

Microbial and human transcriptome in vaginal fluid at midgestation: Association with spontaneous preterm delivery.

Wikstrom T, Abrahamsson S, Bengtsson-Palme J, Ek J, Kuusela P, Rekabdar E Clin Transl Med. 2022; 12(9):e1023.

PMID: 36103557 PMC: 9473488. DOI: 10.1002/ctm2.1023.

References

Shaw J, Diamandis E . A potential role for tissue kallikrein-related peptidases in human cervico-vaginal physiology. Biol Chem. 2008; 389(6):681-8. DOI: 10.1515/BC.2008.069. View

Sales K, Masedunskas A, Bey A, Rasmussen A, Weigert R, List K . Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat Genet. 2010; 42(8):676-83. PMC: 3081165. DOI: 10.1038/ng.629. View

Gorodeski G, Hopfer U, Liu C, Margles E . Estrogen acidifies vaginal pH by up-regulation of proton secretion via the apical membrane of vaginal-ectocervical epithelial cells. Endocrinology. 2004; 146(2):816-24. PMC: 2398721. DOI: 10.1210/en.2004-1153. View

Hantoushzadeh S, Sheikh M, Javadian P, Shariat M, Amini E, Abdollahi A . Elevated vaginal pH in the absence of current vaginal infection, still a challenging obstetrical problem. J Matern Fetal Neonatal Med. 2013; 27(6):582-7. DOI: 10.3109/14767058.2013.823394. View

Park J, Park C, Lockwood C, Norwitz E . Role of cytokines in preterm labor and birth. Minerva Ginecol. 2005; 57(4):349-66. View

OHanlon D, Moench T, Cone R . Vaginal pH and microbicidal lactic acid when lactobacilli dominate the microbiota. PLoS One. 2013; 8(11):e80074. PMC: 3819307. DOI: 10.1371/journal.pone.0080074. View

AVERETTE H, Weinstein G, Frost P . Autoradiographic analysis of cell proliferation kinetics in human genital tissues. I. Normal cervix and vagina. Am J Obstet Gynecol. 1970; 108(1):8-17. DOI: 10.1016/0002-9378(70)90195-x. View

Olkhov-Mitsel E, van der Kwast T, Kron K, Ozcelik H, Briollais L, Massey C . Quantitative DNA methylation analysis of genes coding for kallikrein-related peptidases 6 and 10 as biomarkers for prostate cancer. Epigenetics. 2012; 7(9):1037-45. PMC: 3515013. DOI: 10.4161/epi.21524. View

Vadillo-Ortega F, Estrada-Gutierrez G . Role of matrix metalloproteinases in preterm labour. BJOG. 2005; 112 Suppl 1:19-22. DOI: 10.1111/j.1471-0528.2005.00579.x. View

10.

Borgono C, Michael I, Komatsu N, Jayakumar A, Kapadia R, Clayman G . A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem. 2006; 282(6):3640-52. DOI: 10.1074/jbc.M607567200. View

11.

Naftolin F, Tolis G . Neuroendocrine regulation of the menstrual cycle. Clin Obstet Gynecol. 1978; 21(1):17-29. DOI: 10.1097/00003081-197803000-00003. View

12.

Das S, Allan S . Higher vaginal pH is associated with Neisseria gonorrhoeae and Chlamydia trachomatis infection in a predominantly white population. Sex Transm Dis. 2006; 33(8):527-8. DOI: 10.1097/01.olq.0000230430.60398.e4. View

13.

Leese H . The formation and function of oviduct fluid. J Reprod Fertil. 1988; 82(2):843-56. DOI: 10.1530/jrf.0.0820843. View

14.

Eissa A, Amodeo V, Smith C, Diamandis E . Kallikrein-related peptidase-8 (KLK8) is an active serine protease in human epidermis and sweat and is involved in a skin barrier proteolytic cascade. J Biol Chem. 2010; 286(1):687-706. PMC: 3013028. DOI: 10.1074/jbc.M110.125310. View

15.

Boskey E, Telsch K, Whaley K, Moench T, Cone R . Acid production by vaginal flora in vitro is consistent with the rate and extent of vaginal acidification. Infect Immun. 1999; 67(10):5170-5. PMC: 96867. DOI: 10.1128/IAI.67.10.5170-5175.1999. View

16.

Chow T, Crow M, Earle T, El-Said H, Diamandis E, Yousef G . Kallikreins as microRNA targets: an in silico and experimental-based analysis. Biol Chem. 2008; 389(6):731-8. DOI: 10.1515/BC.2008.071. View

17.

Shaw J, Petraki C, Watson C, Bocking A, Diamandis E . Role of tissue kallikrein-related peptidases in cervical mucus remodeling and host defense. Biol Chem. 2008; 389(12):1513-22. DOI: 10.1515/BC.2008.171. View

18.

Smith M, Lechago J, Wines D, MacDonald R, Hammer R . Tissue-specific expression of kallikrein family transgenes in mice and rats. DNA Cell Biol. 1992; 11(5):345-58. DOI: 10.1089/dna.1992.11.345. View

19.

Huppert J, Bates J, Weber A, Quinn N, Gaydos C . Abnormal vaginal pH and Mycoplasma genitalium infection. J Pediatr Adolesc Gynecol. 2012; 26(1):36-9. PMC: 3552140. DOI: 10.1016/j.jpag.2012.09.005. View

20.

Yu Y, Prassas I, Diamandis E . Putative kallikrein substrates and their (patho)biological functions. Biol Chem. 2014; 395(9):931-43. DOI: 10.1515/hsz-2014-0129. View