LANGERHANS CELLS REQUIRE SIGNALS FROM BOTH TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-1-BETA FOR MIGRATION

The induction phase of contact sensitization is associated with the mo vement of epidermal Langerhans cells (LC) from the skin and their migr ation, via afferent lymphatics, to draining lymph nodes where they acc umulate as immunostimulatory dendritic cells (DC). It has been demonst rated previously that tumour necrosis factor-alpha (TNF-alpha) provide s an important signal for LC migration and that in the absence of this cytokine, movement of LC from the epidermis to regional lymph nodes i s inhibited. Recent evidence indicates that interleukin-1 beta (IL-1 b eta), a cytokine produced in murine epidermis exclusively by LC, may a lso play a role in LC migration. The purpose of the investigations des cribed here was to clarify, using relevant neutralizing anticytokine a ntibodies, the contributions made by TNF-alpha and IL-1 beta to the mi gration of LC from the epidermis. It was found that like anti-TNF-alph a, anti-IL-1 beta administered systemically to mice (by intraperitonea l injection), prior to skin sensitization with the contact allergen ox azolone, resulted in a marked inhibition of DC accumulation in drainin g lymph nodes. It was shown also that anti-IL-1 beta inhibited TNF-alp ha-induced LC migration and DC accumulation and that, in similar fashi on, the stimulation of LC migration and DC accumulation induced by IL- 1 beta was compromised by prior treatment with anti-TNF-alpha. Based u pon these data it is proposed that the stimulation of LC migration in response to skin sensitization requires the receipt by LC of two indep endent signals, one provided by TNF-alpha and the other by IL-1 beta. Morphological analyses of LC in epidermal sheets prepared from animals exposed to these cytokines with or without prior systemic treatment w ith anti-cytokine antibody suggested that the changes induced in LC by TNF-alpha and IL-1 beta may include the altered expression of adhesio n molecules and acquisition of the ability to interact with and pass t hrough the basement membrane.