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Putative functions of tissue kallikrein-related peptidases in vaginal fluid

Key Points

  • Tissue kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases expressed in various tissues and body fluids that are involved in multiple physiological processes

  • Several KLKs are abundantly expressed in the tissues of the female reproductive tract and are present at a high concentration in cervical-vaginal fluid (CVF)

  • pH is a key regulator of KLK activity and limited KLK activity is expected in CVF, owing to its low pH (≤4.5) in healthy women of reproductive age

  • Increased KLK activity is possible when the vaginal pH is elevated, owing to a disturbed vaginal microbiome, decreased oestrogen levels, or mixing of CVF with fluids of increased alkalinity

  • KLKs are presumably involved in proteolytic cascades related to antimicrobial processes, sperm transport, vaginal epithelial desquamation, and preterm premature rupture of membranes, through targeting of known and unknown KLK substrates

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.

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Figure 1: Expression of the 15 tissue kallikrein-related protease (KLK) family members in the tissues of the female reproductive system.
Figure 2: Concentration of the most abundant tissue kallikrein-related proteases (KLKs) in different human biological fluids11.
Figure 3: The role of tissue kallikrein-related proteases (KLKs) in antimicrobial processes in the lower female reproductive tract.
Figure 4: The role of tissue kallikrein-related proteases (KLKs) in cervical and vaginal epithelial desquamation.
Figure 5: The role of tissue kallikrein-related proteases (KLKs) in sperm transport through mucin remodelling.
Figure 6: The role of tissue kallikrein-related proteases (KLKs) in the breakdown of fetal membranes.

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C.M.J.M., S.K.V., K.O., and I.P. researched data for and wrote the article. All authors made substantial contributions to dicussions of content and reviewed and edited the manuscript before submission.

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Muytjens, C., Vasiliou, S., Oikonomopoulou, K. et al. Putative functions of tissue kallikrein-related peptidases in vaginal fluid. Nat Rev Urol 13, 596–607 (2016). https://doi.org/10.1038/nrurol.2016.161

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