Amphotericin B-induced interleukin-1β 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)-1 beta 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-1 beta expression. Furthermore, amphotericin B-induced IL-1 beta expression is attenuated by the calmodulin antagonist calmidazolium, Amphotericin B 5.41 mu M 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-1 beta expression is attenuated. Thus, amphotericin B acts as an ionophore to increase [Ca++](i) and activates calmodulin-mediated expression of IL-1 beta in human monocytes.