Vasoactive intestinal peptide regulates its receptor expression and functions of human keratinocytes via type I...

Vasoactive intestinal peptide has been suggested to play some roles in inflammatory dermatoses such as atopic dermatitis and psoriasis. The aim of this study is to clarify the precise mechanisms of how vasoactive intestinal peptide is implicated in the pathogenesis of these disorders. We investigated the expression of vasoactive intestinal peptide and its receptors in normal human fibroblasts and keratinocytes, as well as in a human epidermal keratinocyte cell line DJM-1, using reverse transcription polymerase chain reaction and northern blotting. Type I VIP receptor mRNA was expressed in normal human keratinocytes and DJM-1 cells, and the latter also expressed type II receptor in lesser amounts. Neither type I nor type II VIP receptor mRNA was detected in fibroblasts, and vasoactive intestinal peptide transcript was not found in any cells examined. Type I VIP receptor mRNA was upregulated by Th1 cytokines (interferon-gamma), Th2 cytokines (interleukin-4), and tumor necrosis factor alpha, as well as vasoactive intestinal peptide itself, suggesting the presence of an autoregulatory loop. Vasoactive intestinal peptide increased cAMP production and cell proliferation of DJM-1 cells, and also induced the production of inflammatory cytokines such as interleukin-6, interleukin-8, and RANTES. The production of cAMP and cytokines was abrogated by a type I VIP receptor selective antagonist, indicating that type I receptor mediates these effects. Overall, these results suggest that upregulation of vasoactive intestinal peptide receptors by cytokines from inflammatory cells in the dermis enhances the proliferation and cytokine production of keratinocytes in response to vasoactive intestinal peptide from nerve endings. This cytokine network around keratinocytes may be involved in the pathogenesis of inflammatory dermatoses.