Proinflammatory cytokine responses in skin and epidermal cells following epicutaneous administration of anticoagulant rodenticide warfarin in rats

Abstract

Context: 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. Materials and methods: Ex vivo production of IL-1 beta, IL-6, TNF-alpha 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 mu g 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-alpha and IL-17; epidermal cells by IL-1 beta and TNF-alpha) except IL-6. Discussion: Along with histomorphological changes, cytokines indicate functional consequences in treated skin. IL-1 beta production, that precede production of TNF-alpha, might be responsible for production of the latter cytokine. Sustained production of IL-1 beta 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. Conclusion: Presented data provide additional new information concerning proinflammatory effects of warfarin.