title: Epithelial proinflammatory response and curcumin-mediated protection from staphylococcal toxic shock syndrome toxin-1.
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.
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Schaefers
authors.forename: Laura M
authors.initials: LM
authors.lastname: Breshears
authors.forename: Michele J
authors.initials: MJ
authors.lastname: Anderson
authors.forename: Ying-Chi
authors.initials: YC
authors.lastname: Lin
authors.forename: Alex E
authors.initials: AE
authors.lastname: Grill
authors.forename: Jayanth
authors.initials: J
authors.lastname: Panyam
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Southern
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Schlievert
authors.forename: Marnie L
authors.initials: ML
authors.lastname: Peterson
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002461:Cell Line, Transformed; D018925:Chemokines / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis; D009092:Mucous Membrane / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology*; D018089:Superantigens / Q000633:toxicity*; D034421:Sus scrofa; D014621:Vagina / Q000187:drug effects / Q000382:microbiology / Q000473:pathology
chemical_list: D001427:Bacterial Toxins; D018925:Chemokines; D004768:Enterotoxins; D018836:Inflammation Mediators; D016209:Interleukin-8; D016328:NF-kappa B; D020011:Protective Agents; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; D003474:Curcumin