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.
Rogers
P D
PD
Department of Clinical Pharmacy Practice, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA. drogers@medicine.umsmed. edu
Kramer
R E
RE
Chapman
S W
SW
Cleary
J D
JD
D000666:Amphotericin B / Q000494:pharmacology*; D000001:Calcimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics*; D007700:Kinetics; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology
D002147:Calmodulin; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D000001:Calcimycin; C031938:calmidazolium; D019284:Thapsigargin; C033170:4-bromo-A-23187; D000666:Amphotericin B; D002118:Calcium