Cleavage/Alteration of Interleukin-8 by Matrix Metalloproteinase-9 in the Female Lower Genital Tract

Abstract

ObjectiveInterleukin-8 (IL-8, CXCL8) plays important roles in immune responses at mucosal sites including in the lower genital tract. Since several types of bacteria produce proteases that cleave IL-8 and many types of bacteria can be present in lower genital tract microbiota, we assessed genital fluids for IL-8 cleavage/alteration.Study DesignGenital fluids collected by lavage from 200 women (23 HIV-seronegative and 177 HIV-seropositive) were tested for IL-8 cleavage/alteration by ELISA.ResultsIL-8 cleaving/altering activity was observed in fluids from both HIV-positive (28%) and HIV-negative women (35%). There was no clear relationship between the activity and the types of bacteria present in the lower genital tract as determined by high-throughput sequencing of the 16S rRNA gene. Protease inhibitors specific for matrix metalloproteinases (MMPs) reduced the activity and a multiplex assay that detects both inactive and active MMPs showed the presence of multiple MMPs, including MMP-1, -3, -7, -8, -9, -10 and -12 in genital secretions from many of the women. The IL-8-cleaving/altering activity significantly correlated with active MMP-9 as well as with cleavage of a substrate that is acted on by several active MMPs.ConclusionsThese studies show that multiple MMPs are present in the genital tract of women and strongly suggest that MMP-9 in genital secretions can cleave IL-8 at this mucosal site. These studies suggest that MMP-mediated cleavage of IL-8 can modulate inflammatory responses in the lower genital tract.

Identification of Cultivable Bacteria in Amniotic Fluid Using Cervicovaginal Fluid Protein Microarray in Preterm Premature Rupture of Membranes

“…In AF, Cobo et al and Park et al have previously reported significant associations between AF IL-8 and MMP-9 with MIAC in women with PPROM [21,22]. Taken together, the data from our group and others [22,24,26] support the importance of MMP-9 and IL-8 in the common pathophysiology of MIAC and ruptured membranes, regardless of whether the source of these two proteins is CVF or AF.…”

“…In the present study, we demonstrated that CVF MMP-9 is a useful non-invasive biomarker for MIAC in PPROM, and that the CVF level of MMP-9 was also significantly correlated with CVF IL-8 (r = 0.410). Similarly, MMP-9 in the lower genital tract fluid has been shown to be involved in the cleavage of IL-8 at this mucosal site, suggesting MMP-mediated cleavage of IL-8 can modulate inflammatory responses in the lower genital tract [26]. In AF, Cobo et al and Park et al have previously reported significant associations between AF IL-8 and MMP-9 with MIAC in women with PPROM [21,22].…”

Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances

“…As one of the most widely investigated MMPs, MMP-9 is a significant protease which plays a vital role in many biological processes, such as wound healing [ 3 , 8 , 38 , 39 , 40 , 41 , 42 , 43 ]. This protease has a broad range of substrates.…”

Role of MMP-9 in epithelial-mesenchymal transition of thyroid cancer

“…It can regulate the structure of ECM by cutting and degrading multiple extracellular matrix proteins through protease hydrolysis [18]. Apart from that, MMP-9 is capable of specifically cutting the extracellular domain on the surface of certain cell proteins to release them from the plasma membrane, and some peptides can also be degraded by MMP-9 outside the cell [19]. The basement membrane contains collagen, such as type IV collagen, so it can be degraded by MMP-9 [20,21].…”