Cimetidine reduces cyclosporine inhibition of interleukin-2 production

Cimetidine has been shown to up-regulate proliferative and cytotoxic immune responses, which are mediated in part by an increase in interleukin-2 (IL-2) production. Cyclosporine achieves its immunosuppressive effect mainly through inhibition of IL-2 production. A recent clinical report of renal allograft recipients with elevated serum creatinine levels while on a histamine type-2 receptor antagonist raised concern whether the cimetidine increase in IL-2 production was counterbalancing the cyclosporine inhibition of IL-2 and thereby increasing alloreactivity to the transplant. We therefore measured IL-2 production of mitogen-stimulated murine spleen cells with or without cimetidine and cyclosporine and in combination of these two drugs. Cimetidine (10(-4) and 10(-5) M) completely reversed the cyclosporine (0.1 ng/ml and 1 ng/ml)-induced 25 and 41% inhibitions of IL-2, respectively. Cyclosporine (10 ng/ml) reduced IL-2 by 64% and cimetidine partially reversed this inhibition to 48%. All cimetidine groups which reduced the cyclosporine effect on IL-2 were statistically significant (P less than 0.05). These data raise concern about the safety of giving histamine type-2 receptor antagonists to allograft recipients without increasing alloreactivity due to a relative increase in IL-2.