The migration of Langerhans cells is an initial event in the sensitization phase of contact sensitivity. Langerhans cells travel from the epidermis to the regional lymph node, and can be variously modulated in the skin where many cytokines are released from epidermal cells, dermal cells, T helper (Th) cells, and other inflammatory cells during the sensitization and elicitation phase of contact dermatitis, and thus induce an altered inflammatory skin reaction. The modulatory effect of the cytokines released in the skin, such as IL-1beta, GM-CSF, and TNF-alpha as epidermal cytokines, IL-2, IL-12, and IFN-gamma as Th1 type cytokines, and IL-4 and IL-10 as Th2 type cytokines, was analyzed using the chemotactic chamber method in this study. Both GM-CSF and TNF-alpha induced the migration of human Langerhans cells in vitro, whereas IL-1beta, IL-2, IL-10, IL-12, and IFN-gamma had no effect on Langerhans cell migration. In contrast, IL-4 inhibited Langerhans cell migration in a dose dependent manner. The inhibitory activity of IL-4 was reversed by both anti-human IL-4 monoclonal antibody and anti-human IL-4 receptor monoclonal antibody. IL-4 inhibited the Langerhans cell migration induced by both TNF-alpha and GM-CSF. Furthermore, anti-TNF-RII monoclonal antibody inhibited both random migration and the migration induced by TNF-alpha, but not that induced by GM-CSF. A reverse-transcriptase-polymerase chain reaction and fluorescence-activated cell sorter analysis revealed that TNF-alpha up-regulated and IL-4 downregulated the TNF receptor II (TNF-RII) expression of Langerhans cells at both the mRNA and the protein levels. The pretreatment of Langerhans cells with TNF-alpha enhanced the migration of Langerhans cells and the expression of TNF-RII. After pretreating Langerhans cells with TNF-alpha, IL-4 inhibited both the migration of Langerhans cells and the expression of TNF-RII in a time dependent manner. These results indicate that IL-4 inhibits the migratory activity of Langerhans cells by downregulating the expression of TNF-RII in human Langerhans cells and thereby modulates the immune response in the skin.