Crucial Role of Phospholipase Cε in Induction of Local Skin Inflammatory Reactions in the Elicitation Stage of Allergic Contact Hypersensitivity

Abstract

Phospholipase Cε (PLCε) is an effector of Ras/Rap small GTPases. We previously demonstrated that PLCε plays a crucial role in development of phorbor ester-induced skin inflammation, which is intimately involved in the promotion of skin carcinogenesis. In this study, we have examined its role in local skin inflammatory reactions during development of contact hypersensitivity toward a hapten 2,4-dinitrofluorobenzene (DNFB). PLCε+/+ and PLCε−/− mice were sensitized with DNFB, followed by a DNFB challenge on the ears. PLCε−/− mice exhibited substantially attenuated inflammatory reactions compared with PLCε+/+ mice as shown by suppression of ear swelling, neutrophil infiltration, and proinflammatory cytokine production. In contrast, the extent and kinetics of CD4+ T cell infiltration showed no difference depending on the PLCε background. Adoptive transfer of CD4+ T cells from the sensitized mice to naive mice between PLCε+/+ and PLCε−/− backgrounds indicated that PLCε exerts its function in cells other than CD4+ T cells, presumably fibroblasts or keratinocytes of the skin, to augment inflammatory reactions during the elicitation stage of contact hypersensitivity. Moreover, dermal fibroblasts and epidermal keratinocytes cultured from the skin expressed proinflammatory cytokines in a PLCε-dependent manner on stimulation with T cell-derived cytokines such as IL-17, IFN-γ, TNF-α, and IL-4. These results indicate that PLCε plays a crucial role in induction of proinflammatory cytokine expression in fibroblasts and keratinocytes at the challenged sites, where infiltrated CD4+ T cells produce their intrinsic cytokines, thereby augmenting the local inflammatory reactions.