HLA class-II molecules present antigen to the immune system and are expressed by normal villous enterocytes. Increased expression occurs in inflammatory bowel and coeliac disease, and it is suggested that cytokines may mediate such increased expression. The effects of the cytokines IFN-gamma and TNF-alpha on epithelial HLA class-II expressions have been studied in adult human jejunal mucosal biopsy specimens cultured in vitro. Specimens from nine patients with normal jejunal histology were cultured for 24 h with IFN-gamma, TNF-alpha, or both. Six of nine patients showed increased HLA-DR and HLA-DP expression after culture with the cytokines. We have demonstrated that these cytokines induce increased epithelial HLA class-II expression in adult jejunal mucosal specimens cultured in vitro, a model that most closely resembles the in vivo state. This provides further evidence that such increased expression occurs secondarily to the products of immunologic activation.