Abstract
Staphylococcus aureus initiates infections and produces virulence factors, including superantigens (SAgs), at mucosal surfaces. The SAg, Toxic Shock Syndrome Toxin-1 (TSST-1) induces cytokine secretion from epithelial cells, antigen presenting cells (APCs) and T lymphocytes, and causes toxic shock syndrome (TSS). This study investigated the mechanism of TSST-1-induced secretion of proinflammatory cytokines from human vaginal epithelial cells (HVECs) and determined if curcumin, an anti-inflammatory agent, could reduce TSST-1-mediated pathology in a rabbit vaginal model of TSS. TSST-1 caused a significant increase in NF-κB-dependent transcription in HVECs that was associated with increased expression of TNF- α, MIP-3α, IL-6 and IL-8. Curcumin, an antagonist of NF-κB-dependent transcription, inhibited IL-8 production from ex vivo porcine vaginal explants at nontoxic doses. In a rabbit model of TSS, co-administration of curcumin with TSST-1 intravaginally reduced lethality by 60% relative to 100% lethality in rabbits receiving TSST-1 alone. In addition, TNF-α was undetectable from serum or vaginal tissue of curcumin treated rabbits that survived. These data suggest that the inflammatory response induced at the mucosal surface by TSST-1 is NF-κB dependent. In addition, the ability of curcumin to prevent TSS in vivo by co-administration with TSST-1 intravaginally suggests that the vaginal mucosal proinflammatory response to TSST-1 is important in the progression of mTSS.
Highlights
Staphylococcus aureus is a significant human pathogen that causes a wide range of diseases, including menstrual toxic shock syndrome
We hypothesized that vaginal mucosal proinflammatory cytokines contribute to toxic shock syndrome (TSS) by an outside-in proinflammatory signaling mechanism, which disrupts the mucosa and allows Toxic Shock Syndrome Toxin-1 (TSST-1) to penetrate into the submucosa and bloodstream
Previous studies were expanded using an unrelated, immortalized human vaginal epithelial cells (HVECs) line constructed from another woman, which was obtained from American Type Culture Collection (ATCC) [23]
Summary
Staphylococcus aureus is a significant human pathogen that causes a wide range of diseases, including menstrual toxic shock syndrome (mTSS). The staphylococcal superantigen (SAg), Toxic Shock Syndrome Toxin-1 (TSST-1), causes the majority of mTSS cases by penetrating the vaginal mucosa and non- crosslinking Major Histocompatibility Complex (MHC) class II molecules with T-cell receptors (TCR) causing massive systemic cytokine release from T cells (IL-2, TNF-b, and IFN-c) and macrophages (IL-1b and TNF-a). SAgs, including TSST-1, induce changes in cellular morphology and secretion of proinflammatory cytokines/chemokines from vaginal, bronchial, nasal, and intestinal epithelial cells [4,5,6,7]. The proinflammatory effect of TSST-1 on vaginal epithelial cells may be critical to mTSS progression as glycerol monolaurate (GML), a non-specific anti-inflammatory agent, protected against TSS in a rabbit vaginal model [8,9]. The vaginal epithelial cell proinflammatory signaling pathways activated in response to TSST-1 are unknown
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