Epithelial cells are the first line of defense against external dangers, and are generally involved in immune regulation by the release of the contents from damaged cells and by de novo production of proinflammatory mediators. However, direct evidence implicating specific keratinocyte signaling pathways in the onset of cutaneous inflammatory diseases is lacking. Genetic alterations of NF-κB and MAPK pathways in the epidermis are reported to be possible causes of psoriasis. TRAF6 is an E3 ubiquitin ligase that governs the downstream NF-κB and MAPK pathways. Here, we demonstrated that Cre-mediated deletion of TRAF6 specifically in keratinocytes resulted in complete unresponsiveness to imiquimod-induced psoriatic dermatitis in mice. Mice lacking TRAF6 in keratinocytes could not activate dendritic cells to produce IL-23 or induce IL-17-producing γδ T cells at the imiquimod-treated sites. On the other hand, Th1-mediated epicutaneous hapten-induced contact hypersensitivity or Th2-mediated papain-induced IgE production was unaffected. Subcutaneous administrations of IL-23 restored IL-17 production from γδ T cells in the mutant animals, suggesting that the induction of IL-23 production is the major TRAF6-dependent contribution of keratinocytes to this process. TRAF6-null keratinocytes showed defective transcriptional response of proinflammatory genes, such as Il1b, Tnf, and Cxcl1, on stimulation with imiquimod. IL-17-induced transcription of the response genes, Il24, Ccl20, and Defb3, of TRAF6-null keratinocytes was also impaired. Therefore, complete abrogation of psoriasiform dermatitis upon epithelial deletion of TRAF6 results from two signaling events: the primary response of keratinocytes and the positive feedback loop induced by IL-17 that is produced by γδ T cells. Thus, these findings conclusively demonstrated that a signaling event in keratinocytes is critical for the establishment of IL-17-dependent inflammation in the skin, and suggest that transcriptional response of epithelial cells contributes to the initiation and propagation of the cutaneous immune response.