FK-506, a potent novel immunosuppressive agent, binds to a cytosolic protein which is distinct from the cyclosporin A-binding protein, cyclophilin.
A novel macrolide antibiotic, FK-506, isolated from Streptomyces tsukubaensis, has been shown to be a potent immunosuppressive agent in vivo and in vitro. FK-506 shares a number of immunosuppressive properties with the cyclic peptide, cyclosporin A (CsA), although 10 to 100 times more potent in this regard. These similarities suggest that both agents may share a similar mechanism(s) of action at the biochemical level. We have identified a cytoplasmic binding protein for FK-506 in the human T cell line, JURKAT, using [3H]FK-506. The FK-506 binding protein has a mr of 10 to 12 kDa (as determined by gel filtration), is heat stable and does not bind CsA. This contrasts with the CsA binding protein, cyclophilin, in that cyclophilin is heat labile and has a mr of 15 to 17 kDa. Our data suggest that FK-506 binds to a low m.w. protein(s) in JURKAT cells, which is distinct from cyclophilin. This protein may mediate the immunosuppressive effects of FK-506 in T cells. In addition, our results suggest that the immunosuppressive activity of FK-506, as with CsA, is mediated by an intracellular mechanism.
Siekierka
J J
JJ
Merck, Sharp, and Dohme Research Laboratories, Department of Immunology Research, Rahway, NJ 07065.
Staruch
M J
MJ
Hung
S H
SH
Sigal
N H
NH
D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D003524:Cyclosporins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D007945:Leukemia, Lymphoid / Q000378:metabolism; D019696:Peptidylprolyl Isomerase; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D013347:Subcellular Fractions / Q000378:metabolism; D016559:Tacrolimus; D014407:Tumor Cells, Cultured / Q000378:metabolism
D002352:Carrier Proteins; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011725:Pyridines; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus