Abstract
BackgroundVaginal epithelial cells have receptors, signal transduction mechanisms, and cytokine secretion capabilities to recruit host defenses against Candida albicans infections. This research evaluates how probiotic lactobacilli affect the defensive epithelial response.MethodsThis study used quantitative reverse transcription-polymerase chain reaction assay (qRT-PCR), flow cytometry, and a multiplex immunoassay to observe changes in the regulation of gene expression related to cytokine responses in the VK2 (E6/E7) vaginal epithelial cell line treated with 17β-estradiol, exposed to probiotic Lactobacillus rhamnosus GR-1® and Lactobacillus reuteri RC-14® and challenged with C. albicans. Data were statistically evaluated by repeated measures analysis of variance and paired t-tests where appropriate.ResultsC. albicans induced mRNA expression of genes related to inflammatory cytokine responses associated with nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signal transduction pathways. 17β-estradiol suppressed expression of interleukin-1α (IL-1α), IL-6, IL-8, and tumor necrosis factor alpha (TNFα) mRNA. Probiotic lactobacilli suppressed C. albicans-induced nuclear factor-kappa B inhibitor kinase kinase alpha (Iκκα), Toll-like receptor-2 (TLR2), TLR6, IL-8, and TNFα, also suggesting inhibition of NF-κB signaling. The lactobacilli induced expression of IL-1α, and IL-1β mRNA, which was not inhibited by curcumin, suggesting that they induce an alternate inflammatory signal transduction pathway to NF-κB, such as the mitogen activated protein kinase and activator protein-1 (MAPK/AP-1) signal transduction pathway. Curcumin inhibited IL-13 secretion, suggesting that expression of this cytokine is mainly regulated by NF-κB signaling in VK2 cells.ConclusionsThe results suggest that C. albicans infection induces pro-inflammatory responses in vaginal epithelial cells, and estrogen and lactobacilli suppress expression of NF-κB-related inflammatory genes. Probiotic lactobacilli may induce IL-1α and IL-1β expression by an alternate signal transduction pathway, such as MAPK/AP-1. Activation of alternate signaling mechanisms by lactobacilli to modify epithelial cell cytokine production may be a mechanism for probiotic modulation of morbidity in vulvovaginal candidiasis.
Highlights
Vaginal epithelial cells have receptors, signal transduction mechanisms, and cytokine secretion capabilities to recruit host defenses against Candida albicans infections
When 17β-estradiol was incubated with the cells alone, there was a significant increase in trans-epithelial electrical resistance (TEER), but when VK2 cells were treated with 17β-estradiol and C. albicans-challenged, the TEER values were significantly reduced (Figure 1)
The L. rhamnosus GR-1 and L. reuteri RC-14 strains are used in commercial probiotic products for maintenance of vaginal health
Summary
Vaginal epithelial cells have receptors, signal transduction mechanisms, and cytokine secretion capabilities to recruit host defenses against Candida albicans infections. Some in vivo experiments have shown that the strains L. rhamnosus GR-1 and L. reuteri RC-14 may be effective treatments for VVC [3] These organisms may partially affect resistance to yeast infections by modulating the pro-inflammatory responses of vaginal epithelial cells to the fungus. The vaginal epithelial cell can be considered part of this innate defense system, as it is capable of producing pro-inflammatory cytokines. These cells are known to send Langerhans cell recruitment signals in the form of the CCL20 chemokine [6] and they express other immune recruitment molecules [7]. Recognition of surface molecular patterns of probiotic bacteria by VEC may account for some of their ability to modify host responses to C. albicans
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