title: Identification of novel mechanisms involved in generating localized vulvodynia pain.
abstract: OBJECTIVE
  Our goal was to gain a better understanding of the inflammatory pathways affected during localized vulvodynia, a poorly understood, common, and debilitating condition characterized by chronic pain of the vulvar vestibule.
  
  
  METHODS
  In a control matched study, primary human fibroblast strains were generated from biopsies collected from localized provoked vulvodynia (LPV) cases and from age- and race-matched controls. We then examined intracellular mechanisms by which these fibroblasts recognize pathogenic Candida albicans; >70% of vulvodynia patients report the occurrence of prior chronic Candida infections, which is accompanied by localized inflammation and elevated production of proinflammatory/pain-associated interleukin (IL)-6 and prostaglandin E2 (PGE2). We focused on examining the signaling pathways involved in recognition of yeast components that are present and abundant during chronic infection.
  
  
  RESULTS
  Dectin-1, a surface receptor that binds C albicans cell wall glucan, was significantly elevated in vestibular vs external vulvar cells (from areas without pain) in both cases and controls, while its abundance was highest in LPV cases. Blocking Dectin-1 signaling significantly reduced pain-associated IL-6 and PGE2 production during the response to C albicans. Furthermore, LPV patient vestibular cells produced inflammatory mediators in response to low numbers of C albicans cells, while external vulvar fibroblasts were nonresponsive. Inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (proinflammatory transcription factor) nearly abrogated IL-6 and PGE2 production induced by C albicans, in keeping with observations that Dectin-1 signals through the nuclear factor kappa-light-chain-enhancer of activated B cells pathway.
  
  
  CONCLUSIONS
  These findings implicate that a fibroblast-mediated proinflammatory response to C albicans contributes to the induction of pain in LPV cases. Targeting this response may be an ideal strategy for the development of new vulvodynia therapies.
authors: Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY.
authors: Megan L
authors: ML
authors: Falsetta
authors: Department of Obstetrics and Gynecology, School of Medicine and Dentistry, University of Rochester, Rochester, NY.
authors: David C
authors: DC
authors: Foster
authors: Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY.
authors: Collynn F
authors: CF
authors: Woeller
authors: Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY.
authors: Stephen J
authors: SJ
authors: Pollock
authors: Department of Obstetrics and Gynecology, School of Medicine and Dentistry, University of Rochester, Rochester, NY.
authors: Adrienne D
authors: AD
authors: Bonham
authors: Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, NY.
authors: Constantine G
authors: CG
authors: Haidaris
authors: Department of Obstetrics and Gynecology, School of Medicine and Dentistry, University of Rochester, Rochester, NY.
authors: Christopher J
authors: CJ
authors: Stodgell
authors: Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY; Department of Obstetrics and Gynecology, School of Medicine and Dentistry, University of Rochester, Rochester, NY; Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, NY. Electronic address: richard_phipps@urmc.rochester.edu.
authors: Richard P
authors: RP
authors: Phipps
mesh_terms: D000328:Adult; D002181:Candidiasis, Vulvovaginal / Q000503:physiopathology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D056650:Vulvodynia / Q000382:microbiology / Q000503:physiopathology*; D000099181:Dectin-1
chemical_list: D015232:Dinoprostone; D015850:Interleukin-6; D037181:Lectins, C-Type; D016328:NF-kappa B; D000099181:Dectin-1
keywords: Dectin-1; cytokine; fibroblast; inflammation; interleukin 6; prostaglandin; vulvodynia