Rapamycin but not FK506 inhibits the proliferation of mononuclear phagocytes induced by colony-stimulating factors.
FK506, CsA, and rapamycin are potent inhibitors of T lymphocyte activation; relatively little is known of their effects on cells of the monocyte/macrophage lineage. Studies were undertaken to determine the effects of these drugs on the proliferative response of bone marrow-derived mononuclear phagocytes (BMMP) to CSFs. Rapamycin inhibited the proliferation of BMMP cultured in the presence of 10% L cell-conditioned medium, used as a source of macrophage CSF. The inhibition by rapamycin was dose dependent and apparent at concentrations of 0.1 nM or greater. In a similar fashion, rapamycin inhibited the proliferation of BMMP stimulated by the recombinant forms of murine IL-3 and murine granulocyte-macrophage CSF, and human macrophage CSF. In contrast, neither FK506 nor CsA at concentrations as high as 1000 nM diminished the proliferation of BMMP cultured under identical conditions. FK506, but not CsA, blocked the inhibitory effects of rapamycin on the response of BMMP to CSFs. In summary, these data indicate that rapamycin inhibits the proliferation of BMMP in response to CSFs. These results imply that patients receiving rapamycin, but not FK506 or CsA, may have an impaired ability to generate a functional mononuclear phagocyte population.
Cooper
M H
MH
Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania.
Gregory
S H
SH
Starzl
T E
TE
Wing
E J
EJ
D000818:Animals; D001854:Bone Marrow Cells; D002452:Cell Count; D002455:Cell Division; D003115:Colony-Stimulating Factors / Q000037:antagonists & inhibitors*; D003208:Concanavalin A / Q000494:pharmacology; D017077:Culture Media, Conditioned; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010586:Phagocytes / Q000187:drug effects*; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D003115:Colony-Stimulating Factors; D017077:Culture Media, Conditioned; D011090:Polyenes; D013778:Tetrazolium Salts; D013844:Thiazoles; D014316:Tritium; D003208:Concanavalin A; D016572:Cyclosporine; C022616:thiazolyl blue; D013936:Thymidine; D020123:Sirolimus; D016559:Tacrolimus