title: Proinflammatory cytokine responses in skin and epidermal cells following epicutaneous administration of anticoagulant rodenticide warfarin in rats.
abstract: BACKGROUND
  Dermal toxicity of coumarin anticoagulant rodenticides, such as warfarin, represents potential risk for workers handling these agents and for individuals applying easily available rodenticides in their households as well.
  
  
  OBJECTIVE
  In this study, proinflammatory effects of repeated epicutaneous administration of warfarin in rats were explored by examining inflammatory cytokine skin responses.
  
  
  METHODS
  Ex vivo production of IL-1β, IL-6, TNF-α and IL-17 by skin explants and by epidermal cells isolated by enzyme (dispase/trypsin) digestion from skin repeatedly (once a day, three consecutive days) exposed to 10 µg of warfarin was measured 24 h and 72 h following the last warfarin application by ELISAs for respective rat cytokines.
  
  
  RESULTS
  Warfarin treatment resulted in histological changes, but skin or epidermal cell viability were not compromised, judging by MTT reduction assay. Both skin and epidermal cells responded to administration of this agent by production of all examined inflammatory cytokines (skin explants by TNF-α and IL-17; epidermal cells by IL-1β and TNF-α) except IL-6.
  
  
  CONCLUSIONS
  Along with histomorphological changes, cytokines indicate functional consequences in treated skin. IL-1β production, that precede production of TNF-α, might be responsible for production of the latter cytokine. Sustained production of IL-1β suggests persistence of epidermal cell stimulation or existence of some amplification mechanisms. Requirements for T cells seem to exist concerning epidermal cell IL-17 production.
  
  
  CONCLUSIONS
  Presented data provide additional new information concerning proinflammatory effects of warfarin.
authors.affiliation: Department of Ecology, Institute for Biological Research "Sinisa Stankovic" , University of Belgrade, Belgrade , Serbia .
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Popov Aleksandrov
authors.forename: Marina
authors.initials: M
authors.lastname: Tusup
authors.forename: Ivana
authors.initials: I
authors.lastname: Mirkov
authors.forename: Jelena
authors.initials: J
authors.lastname: Djokic
authors.forename: Marina
authors.initials: M
authors.lastname: Ninkov
authors.forename: Lidija
authors.initials: L
authors.lastname: Zolotarevski
authors.forename: Dragan
authors.initials: D
authors.lastname: Kataranovski
authors.forename: Milena
authors.initials: M
authors.lastname: Kataranovski
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051381:Rats; D012378:Rodenticides / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D016207:Cytokines; D018836:Inflammation Mediators; D012378:Rodenticides
keywords: Epidermal cells; IL-17 production; IL-1β; IL-6; TNF-α; rats; skin; warfarin