Cutaneous Cytokine Expression: Induction by Chemical Allergen and Paracrine Regulation

There is increasing evidence that epidermal cytokines play an essential role during the induction of cutaneous immune responses. In the current investigations, we have compared the pattern of cytokines provoked by exposure to allergen with that stimulated by epidermal cytokines and paracrine regulation of cytokine expression. The kinetics of cytokine-induced changes in cutaneous expression of the cytokines interleukin (IL)-1β, tumor necrosis factor α (TNF-α), and IL-6 have been measured at the protein level. These data confirm that exposure to chemical allergen results in the sequential up-regulation of epidermal cytokines, with a rapid and relatively transient induction of TNF-α protein expression, followed by a more sustained increase in IL-6 production. Intradermal administration of recombinant murine TNF-α and IL-1β each stimulated increases in cutaneous IL-6 protein, although with different tempos. Treatment with TNF-α provoked a rapid (within 2 h) increase in IL-6 expression, whereas IL-1β-induced changes in IL-6 had a more delayed tempo. IL-1β-induced IL-6 production was dependent upon expression of TNF-α such that systemic pretreatment of mice with neutralizing anti-TNF-α antibody markedly inhibited the subsequent induction of cutaneous IL-6 induced by intradermal injection of IL-1β. Thus, intradermal administration of IL-1β apparently induces a similar sequence of events in the skin to that provoked by topical exposure to allergen: up-regulation of IL-6 in a TNF-α-dependent manner. However, treatment with neither allergen nor TNF-α affected the total cumulative levels of cutaneous IL-1β. These data demonstrate that topical exposure to allergen results in the ordered expression of key epidermal cytokines and that the increased bioavailability of each cytokine in turn regulates subsequent cytokine expression. Furthermore, these data suggest that it is the availability of bioactive IL-1β, not changes in total IL-1β expression in the skin, that is the critical factor in IL-1β-dependent events occurring following topical exposure to allergen.