This study reports the roles of extracellular superoxide dismutase (EC-SOD) in the cutaneous inflammation and hyperplasia with 120-tetradecanoylphorbol-3-acetate (TPA) application in EGSOD transgenic mice (Tg EGSOD). Topical double TPA treatment induced the various inflammatory changes including the epidermal thickness, elevated the PCNA-labeling index, the edema formation, and increased production of hydrogen peroxide (H2O2) in wild type mice (WT). These changes were markedly suppressed in TPA-treated Tg EGSOD. The expressions of the inflammatory cytokines, IL-1 alpha and IL-1 beta, were reduced in the TPA-treated Tg EGSOD compared with those in TPA-treated WT. The expression of IL-1 alpha was significantly increased in the skin of TPA-treated WT, especially in the basal and suprabasal layers, but it was restricted focally in basal layer of the skin of TPA-treated Tg EGSOD. The number of infiltrating inflammatory cells and the IL-1 beta expressing cells was obviously reduced in TPA-treated Tg EGSOD in comparison with TPA-treated WT. The result suggests that EGSOD might play an important role in the suppression of TPA-induced cutaneous inflammation and epidermal hyperplasia by regulating the expression of IL-1 alpha and IL-1 beta, although the mechanisms remain to be elucidated. (c) 2006 Elsevier Inc. All rights reserved.