Cytokine production was investigated in oral keratinocytes and tissue-infiltrated mononuclear cells (TIMC) obtained from patients with oral lichen planus (OLP). The numbers of cells producing interleukin (IL)-1 beta, IL-4, IL-6, granulocyte colony-stimulating factor, and tumor necrosis factor-alpha per 10(4) cells in keratinocytes from patients with OLP were determined by enzyme-linked immunospot assay. These levels were two to threefold greater than those in keratinocytes from chronically inflamed gingiva and 10 to 20-fold of those from the intact gingiva. The concentrations of these cytokines in the culture supernatants of keratinocytes were correlated with the number of cytokine-producing cells. Compared with TIMC in the gingiva and peripheral blood mononuclear cells, TIMC in OLP were more cytokine-productive, with larger numbers of cytokine-producing cells that expressed more cytokine messengers. More IL-6, IL-2, and IL-10 were generated from TIMC in OLP, whereas less granulocyte colony-stimulating factor was generated. After pretreatment with IL-2, TIMC from OLP patients generated more IL-6 than did peripheral blood mononuclear cells, and IL-4-pretreated TIMC from the patients released larger amounts of IL-2, IL-6, and IL-10. These results indicate that keratinocytes play a critical role in OLP through production of large amounts of cytokines, that TIMC are stimulated in situ and differentiated to produce cytokines characteristic of OLP, and that the inflammatory condition of OLP is determined by the local cytokine network.