PHARMACOLOGICAL MODULATION OF INTERLEUKIN-1 EXPRESSION BY AMPHOTERICIN B-STIMULATED HUMAN MONONUCLEAR-CELLS

Fever and chills occur frequently with amphotericin B (AB) administration, but the mechanism that causes these reactions has not been definitively established. A variety of proinflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor, have been shown to be important mediators of fever. In order to clarify the cellular and biochemical responses associated with AB-induced fever, the experiments described sought to (i) establish whether human mononuclear cells exposed to AB in vitro expressed IL-1-beta, (ii) evaluate whether clinically used premedications for fever prophylaxis in AB-treated patients were effective in down-regulating IL-1-beta-expression in vitro, (iii) evaluate whether methylxanthine agents with immunomodulatory actions effected in vitro IL-1-beta-expression, and (iv) define the dose and time dependency of the modulating effects. Peripheral blood mononuclear cells were isolated by density centrifugation and resuspended to 10(6) cellS per ml in culture wells of Linbro plates. When cocultured for 2 h with human mononuclear cells, both Escherichia coli lipopolysaccharide and AB stimulated IL-1-beta-expression in a dose-related fashion. AB-induced IL-1-beta-expression was suppressed by hydrocortisone (HC), pentoxifylline, and an investigational theobromine, A81-3138, in a linear, dose-related manner. In contrast, indomethacin, meperidine, and diphenhydramine had no effect on IL-1-beta-expression. Our in vitro data indicate that serum HC concentrations of greater than 1 to 2-mu-g/ml may be sufficient to modulate IL-1-beta-expression. Pentoxifylline and A81-3138 may also be effective in modulating IL-1-beta-expression by mononuclear cells at concentrations achievable in serum. These new agents may prove to be effective alternatives to HC or may be added with HC to suppress febrile reactions secondary to AB administration. Clinical studies with pentoxifylline as a premedication for AB seem warranted.