The mechanisms of SAg stimulation of cytokines from epithelial cells are not well characterized. In this study, we observed a proinflammatory response induced by TSST-1 from an immortalized HVEC line obtained from ATCC and determined that the transcription factor NF-kB is activated in HVECs in response to TSST-1.Theactivationof NF-kB is likely responsiblefor the observed cytokine production as many of the TSST-1-induced cytokines are known to be regulated by NF-kB. These cytokines/chemokines are responsible for migration of immune cells to the vaginal mucosa. Progression of mTSS occurs as these immune cells are activated in a non-antigen specific manner by the superantigenic property of TSST-1. The receptor and signaling pathway responsible for the TSST-1-induced cytokine response in HVECs remain poorly characterized and are currently under investigation. The importance of the inflammatory response at mucosal interfaces suggests that local anti-inflammatory compounds may be of use in the prevention of disease. Curcumin is a component of the Indian spice Turmeric that has anti-inflammatory, anti-angiogenesis, and antimicrobial properties. Curcumin was chosen as a potential anti-TSS agent because it is known to block cytokine-mediated NF-kB activation and proinflammatory gene expression by inhibiting inhibitory factor I-kB kinase activity. In addition, the proinflammatory effects of SAgs on immune cells, such as SEA- and SEB-induced cytokine production from PBMCs and SE-induced fever in rabbits, are inhibited by curcumin. Inhibition of IL-8 production by curcumin from ex vivo porcine vaginal explants indicates that curcumin is anti-inflammatory at the mucosal surface. The doses effective in reducing IL-8 were far lower than doses that are toxic to the tissue, suggesting a wide therapeutic window. Curcumin significantly decreased TSST-1induced lethality in rabbits by 60% suggesting that inhibition of inflammation at the mucosal surface has therapeutic potential. TNF-a, a major mediator of TSS, was undetectable from serum or vaginal tissue of surviving curcumin-treated rabbits. The dose of curcumin used in the rabbit model was higher than the minimum effective dose in the full thickness porcine tissue model but lower than the highest dose tested in the porcine tissue toxicity experiment. In other words, the in vivo rabbit experiment was performed using a concentration of curcumin within the therapeutic range identified using the porcine ex vivo model. Therefore, we believe that curcumin concentrations in this range are safe for topical vaginal application. Curcumin has previously been shown to reduce inflammation. For example, orally administered curcumin inhibited Klebsiella pneumoniae-induced neutrophil infiltration into lung tissue and local TNF-a production and diminished the production of proinflammatory proteins in a murine lung model of infection.