Epidermal keratinocytes, immune cells, and sensory nerves all contribute to immune balance and skin homeostasis. Keratinocyte's release of GFs, neuromodulators, and immune activators is particularly important because each can evoke local (skin) and systemic (ie, immune and neural) responses that can initiate and exacerbate skin pathophysiology. From studies of skin and neural GFs, we hypothesized that neurturin (Nrtn), a member of the GDNF family that is expressed in the skin, has particular importance in this process. In this study, we examine how elevation of Nrtn in skin keratinocytes impacts early cytokine expression in response to complete Freund's adjuvant-mediated inflammation. Nrtn-overexpressing mice and wild-type mice injected with Nrtn exhibit an enhanced level of TNFα and IL-1β cytokines in the skin, a response previously shown to support healing. In vitro assays suggest that one source of the Nrtn-induced TNFα increase is keratinocytes, which are shown to express Nrtn and mRNAs encoding the Nrtn receptors GFRα2, Ret, ITGB1, and NCAM. These findings support the contribution of keratinocyte-derived Nrtn as an autocrine/paracrine factor that acts as a first-line defense molecule that regulates the initial cytokine response to inflammatory challenge.