The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism.
Amphotericin B is the most effective drug for treating many life-threatening fungal infections. Amphotericin B administration is limited by infusion-related toxicity, including fever and chills, an effect postulated to result from proinflammatory cytokine production by innate immune cells. Because amphotericin B is a microbial product, we hypothesized that it stimulates immune cells via Toll-like receptors (TLRs) and CD14. We show here that amphotericin B induces signal transduction and inflammatory cytokine release from cells expressing TLR2 and CD14. Primary murine macrophages and human cell lines expressing TLR2, CD14, and the adapter protein MyD88 responded to amphotericin B with NF-kappaB-dependent reporter activity and cytokine release, whereas cells deficient in any of these failed to respond. Cells mutated in TLR4 were less responsive to amphotericin B stimulation than cells expressing normal TLR4. These data demonstrate that TLR2 and CD14 are required for amphotericin B-dependent inflammatory stimulation of innate immune cells and that TLR4 may also provide stimulation of these cells. Our results provide a putative molecular basis for inflammatory responses elicited by amphotericin B and suggest strategies to eliminate the acute toxicity of this drug.
Sau
Keya
K
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Mambula
Salamatu S
SS
Latz
Eicke
E
Henneke
Philipp
P
Golenbock
Douglas T
DT
Levitz
Stuart M
SM
D048868:Adaptor Proteins, Signal Transducing; D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D018950:Lipopolysaccharide Receptors / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D048868:Adaptor Proteins, Signal Transducing; D000935:Antifungal Agents; D000943:Antigens, Differentiation; D007375:Interleukin-1; D018950:Lipopolysaccharide Receptors; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000666:Amphotericin B