BACKGROUND Uremia produces a wide range of abnormalities of the immune system. Blood-membrane interaction in hemodialysis results in activation and severe dysfunction of peripheral blood mononuclear cells (PBMC). However, the question of whether the use of different dialytic membranes may improve PBMC dysfunctions remains unanswered. METHODS To address this issue, the spontaneous interleukin (IL)-6, IL-8 and monocyte chemotactic peptide-1 (MCP-1) gene expression and protein release were studied in PBMC isolated from 7 healthy subjects, 8 uremic patients on conservative therapy and 8 uremic patients undergoing subsequent one month periods of hemodialysis with cuprophan (CU) and high-flux noncomplement activating membranes, polymethylmethacrylate (PMMA) and polyamide (PA). At the end of each period of treatment, PBMC were harvested at the beginning (T0) and after 180 minutes of dialysis (T180), and then were cultured in complete medium. IL-6, IL-8 and MCP-1 mRNA expression were studied by RT-PCR. In addition, MCP-1 gene expression was evaluated also by in situ hybridization. Cytokines released in the supernatant were measured by ELISA. RESULTS Compared to the control group, PBMC from uremic patients on conservative therapy and treated by CU showed a clear reduction in the cytokine release, while PMMA and PA membranes were able to normalize IL-6, IL-8 and MCP-1 protein concentration, which had been reduced by CU treatment. Interestingly, at T0, mRNA expression for all three cytokines was increased in the patients treated by CU, when compared to the control group and the uremic patients on conservative therapy. A further up-regulation was observed at T180. PMMA and PA treatment, despite increasing the cytokine secretion, significantly reduced the dialysis-induced cytokine gene expression. CONCLUSIONS PBMC exposure to CU membranes results in cytokine mRNA overexpression associated with a paradoxically reduced protein release. In contrast, long-term hemodialysis with synthetic high-flux membranes reduces IL-6, IL-8 and MCP-1 gene expression and improves the ability of PBMC to secrete these cytokines. The reduced cytokine secretion during bioincompatible dialysis may reflect a PBMC adaptation that protects uremic patients against the inflammatory effects of persistent cytokine release.