Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosisfactor-alpha- and IL-1 beta-dependent mechanism

Following skin sensitization a proportion of epidermal Langerhans cells (LC ) are stimulated to leave the skin and to migrate, via efferent lymphatics, to draining lymph nodes where they accumulate as immunostimulatory dendrit ic cells (DC). It has been demonstrated previously that tumour necrosis fac tor-alpha (TNF-alpha), an inducible product of epidermal keratinocytes, and interleukin (IL)-1 beta produced exclusively by LC in murine epidermis. pr ovide important signals for the initiation of this response. Recently. it h as been demonstrated that IL-18. a cytokine produced by both LC and keratin ocytes within the epidermis, may also participate in immune responses induc ed following skin sensitization. In the present investigations. the ability of IL-18 to contribute to the regulation of LC migration and the accumulat ion of DC in draining lymph nodes has been examined. It was round that, lik e IL-1 beta, IL-18 administered intradermally to mice resulted in a signifi cant reduction in epidermal major histocompatibility complex (MHC) class II + LC densities and a marked increase in lymph node DC numbers, Using neutra lizing anti-TNF-alpha and blocking anti-type I IL-1 receptor (IL-1RI) antib odies. it was shown also that the: induction by IL-18 of both LC mobilizati on and DC accumulation in regional lymph nodes was dependent upon availabil ity of TNF-alpha and the integrity of IL-1RI signalling. Furthermore, using IL-1 beta converting enzyme (caspase-1) knockout mice, IL-18-induced LC mi gration was found to have a mandatory requirement For active IL-1 beta. Imp ortantly, not only was IL-18 able to contribute to the regulation of LC mig ration, it was found to be essential fur the manifestation of these process es in response to topical sensitization with the contact allergen oxazolone .