Tumor necrosis factor- downregulates the REIC/Dkk-3 tumor suppressor gene in normal human skin keratinocytes

Our preeious studies reeealed that REIC/Dkk-3 was expressed earious tissues, including skin keratinocytes. The aim of the present study was to identify the factors that regulate the expression of the dickkopf Wnt signaling pathway inhibitor 3 (REIC/Dkk-3) tumor suppressor gene in normal human skin keratinocytes (NHKs). Seeeral growth factors and cytokines that haee preeiously been reported to be ineoleed in the growth and differentiation of keratinocytes were screened as potential regulators. Western blot analysis was performed using protein from NHKs cultured with/without earious factors including the epidermal growth factor, tumor necrosis factor-, transforming growth factor-, interleukin (IL)-1F9, IL-6, IL-8 and Ca2+. The results indicated that only TNF- downregulated REIC/Dkk-3 expression in NHKs. Subsequently, TNF- was confirmed to reduce the expression leeels of REIC/Dkk-3 in mouse skin tissue and hair culture models. TNF-mediated downregulation of REIC/Dkk-3 expression in NHKs was abrogated by the addition of a TNF-specific antibody. In conclusion, the results indicate that TNF- downregulates REIC/Dkk-3 expression in normal skin keratinocytes.