Central to the immunosuppressive properties of cyclosporine is a drug imposed blockade of the interleukin-2 gene activation. As IL-6 stimulates antigen-activated T cells to release IL-2, we examined the influence of CsA on IL-6 gene expression and IL-6-supported T cell proliferation. Northern blot analysis revealed that CsA failed to abolish IL-6 gene expression in mitogen-activated peripheral blood mononuclear cells. In fact, increased IL-6 gene transcription and increased release of IL-6 bioactivity were detected using mitogen-activated PBMCs cultured with CsA doses (200-800 ng/ml) only slightly in excess of the minimal antiproliferative dose. CsA completely abrogated the IL-6-stimulated proliferative responses of macrophage-depleted T cells stimulated with polyvalent anti-CD3 monoclonal antibodies. It is interesting that CsA-treated patients evidence an increased incidence of polyclonal lymphoproliferative disorders and B cell lymphomas. As IL-6 fosters B cell activation and growth of EBV-transformed B cells, excessive CsA doses may support development of EBV-transformed B cell lymphomas via superinduction of the IL-6 gene.