Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription.
Investigations of the actions and interactions of the immunophilin ligands FK506, cyclosporin A (CsA), rapamycin, and 506BD suggest that complexes of FK506 with an FK506-binding protein or of CsA with a cyclophilin (CsA-binding protein) inhibit the T-cell receptor-mediated signal transduction that results in the transcription of interleukin 2. Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model. Both FK506 and CsA inhibit receptor-mediated exocytosis (CsA IC50 = 200 nM; FK506 IC50 = 2 nM) without affecting early receptor-associated events (hydrolysis of phosphatidylinositol, synthesis and release of eicosanoids, uptake of Ca2+). In contrast, rapamycin and 506BD, which share common structural elements with FK506, by themselves have no effect on IgE receptor-mediated exocytosis. Both compounds, however, prevent inhibition by FK506 but not by CsA. Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types. These results suggest the existence of a common step in cytoplasmic signaling in T cells and mast cells that may be part of a general signaling mechanism.
Hultsch
T
T
Allergic Diseases Section, National Institutes of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892.
Albers
M W
MW
Schreiber
S L
SL
Hohman
R J
RJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D001095:Arachidonic Acids / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D003524:Cyclosporins / Q000378:metabolism / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects*; D007073:Immunoglobulin E / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D010716:Phosphatidylinositols / Q000378:metabolism; D011090:Polyenes / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011961:Receptors, Fc / Q000187:drug effects / Q000502:physiology*; D017455:Receptors, IgE; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus; D016559:Tacrolimus; D014158:Transcription, Genetic / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D000944:Antigens, Differentiation, B-Lymphocyte; D001095:Arachidonic Acids; D002352:Carrier Proteins; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D008024:Ligands; D010716:Phosphatidylinositols; D011090:Polyenes; D011961:Receptors, Fc; D017455:Receptors, IgE; D012701:Serotonin; D007073:Immunoglobulin E; D002118:Calcium; D020123:Sirolimus; D016559:Tacrolimus