Amphotericin B-induced interleukin-1beta expression in human monocytic cells is calcium and calmodulin dependent

Amphotericin B remains the agent of choice for treatment of severe fungal infections. Its use is hindered by adverse effects, including infusion-related fever, chills, and hypotension, as well as nephrotoxicity with secondary anemia, hypokalemia, and hypomagnesemia. Amphotericin B-induced transcription and expression of interleukin (IL)-1beta by human monocytes is believed to be involved in mediating infusion-related adverse effects. It is shown here that agents that increase intracellular calcium [Ca++]i (A23187 and thapsigargin) in human monocytic cells also induce IL-1beta expression. Furthermore, amphotericin B-induced IL-1beta expression is attenuated by the calmodulin antagonist calmidazolium. Amphotericin B 5.41 microM increases [Ca++]i by up to 300 nM in these cells. In the presence of a nominal calcium buffer or EGTA, amphotericin B-induced IL-1beta expression is attenuated. Thus, amphotericin B acts as an ionophore to increase [Ca++]i and activates calmodulin-mediated expression of IL-1beta in human monocytes.