Activation of Ca2+ signaling in neutrophils by the mast cell-released immunophilin FKBP12.
The immunophilins of the FK506-binding protein (FKBP) family are intracellular proteins that bind the immunosuppresants FK506 and rapamycin. In this study we show that HMC-1 mast cells sensitized with IgE release FKBP12 upon stimulation with anti-IgE. The release is rapid and not affected by actinomycin D or cycloheximide, suggesting that it is due to exocytosis from a storage compartment. FKBP12 from HMC-1 mast cells exhibits biological activity. When applied extracellularly to human neutrophils, it induces transient changes in the intracellular Ca2+ concentration ([Ca2+]i) due to Ca2+ release from intracellular stores. Inhibition of [Ca2+]i changes by ruthenium red and ryanodine indicates that ryanodine receptor/Ca2+ release channels are involved in FKBP12-induced Ca2+ signaling. Neutrophil activation by mast cell-derived FKBP12 is prevented by complexing FKBP12 with FK506 or rapamycin. These results demonstrate that extracellular FKBP12 functions as a cytokine in cell-to-cell communication. They further suggest a pathophysiological role for FKBP12 as a mediator in immediate or type I hypersensitivity and may have implications for novel therapeutic strategies in the treatment of allergic disorders with FK506 and rapamycin.
Bang
H
H
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Germany.
Müller
W
W
Hans
M
M
Brune
K
K
Swandulla
D
D
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005089:Exocytosis; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006636:Histamine Release / Q000502:physiology; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology*; D011090:Polyenes / Q000494:pharmacology; D012430:Ruthenium Red / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D011090:Polyenes; D012430:Ruthenium Red; D022021:Tacrolimus Binding Proteins; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus