Involvement of tumor necrosis factor (TNF)-alpha in phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin edema in mice

Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ear induced a prolonged skin inflammation. Histological analysis revealed that the early stage (approximately 3 h) and later stage (6-24 h) of the skin reaction are characterized by dermal edema and cell accumulation, respectively. Topical application with TPA also induced increase in the level of TNF-alpha and prostagrandin E2 (PGE2) at the application site. The increase of TNF-alpha was transient with a peak at approximately 5 h, followed by a gradual elevation of PGE2 level in the skin. An in vitro study with human keratinocytes as well as immunohistochemical analysis suggested that TNF-alpha induction in the skin might be produced by epidermis treated with TPA. Administration of a cyclooxygenase inhibitor indomethacin inhibited the later stage of the TPA-induced edema. In contrast, TNF-alpha antagonist etanercept inhibited exclusively the early stage of the reaction. Taken together, these data demonstrate that the prolongation of the skin inflammation induced by TPA may be due to the sequential production of proinflammatory mediators such as eicosanoids and cytokines, and show for the first time the importance of TNF-alpha in the TPA-induced dermatitis especially at the stage where dermal edema is significant.