The interaction of interleukin-6 (IL-6) with its receptor (IL-6R) is not well understood. In the present study, we investigated the effect of different immunosuppressive agents on the expression of the couple IL-6/IL-6R on cultured lymphocytes and monocytes. IL-6 in culture supernatants from cultured monocytes were analyzed by ELISA. The expression of IL-6R was studied by flow cytometry. Dexamethazone, cyclosporin (CyA), and FK 506 at immunosuppressive concentrations induced a dose-dependent inhibition of IL-6 secretion from adherent monocytes (MO) stimulated with phytohemagglutinin (PHA). Dexamethazone was the most effective agent in inhibiting IL-6 secretion, while the inhibitory effect observed with 1 ng/ml FK 506 was comparable with that obtained with 100 ng/ml CyA. Unstimulated MO strongly expressed IL-6R (80% positive cells). Stimulation of MO with PHA resulted in a significant downregulation of IL-6R expression. Treatment of PHA-stimulated adherent MO with different concentrations of CyA and FK 506 induced a restoration of IL-6R expression. FK 506 was 100 time more effective in restoring IL-6R than CyA. This restoration of IL-6R was incomplete. FK 506, CyA, and steroids may exert their immunosuppressive effect by inhibiting IL-6 secretion and partially restoring MO IL-6R, which may be important in protecting the cell target against IL-6 autocrine stimulation.