Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo.
Rapamycin (RAPA) is a potent immunosuppressive macrolide hitherto believed to mediate its action primarily via suppression of lymphocyte responses to interleukin 2 (IL-2) and other growth factors. We show here that this view is incomplete and provide evidence that RAPA suppresses the functional activation of dendritic cells (DCs) both in vitro and in vivo. In vitro, RAPA inhibits IL-4-dependent maturation and T-cell stimulatory activity of murine bone marrow-derived DCs. These effects are associated with posttranscriptional down-regulation of both subunits of the IL-4 receptor complex (CD124, CD132) and are mediated via binding of RAPA to its intracellular receptor FK506-binding protein 12 (FKBP12). In vivo, RAPA impairs steady-state DC generation and fms-like tyrosine 3 kinase ligand (Flt3L)-induced DC mobilization. In addition, in vivo administration of RAPA impairs DC costimulatory molecule up-regulation, production of proinflammatory cytokines, and T-cell allostimulatory capacity. These novel findings have implications for RAPA-based therapy of chronic DC-triggered autoimmune diseases, transplant rejection, and hematologic malignancies with activating Flt3 mutations.
Hackstein
Holger
H
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Taner
Timucin
T
Zahorchak
Alan F
AF
Morelli
Adrian E
AE
Logar
Alison J
AJ
Gessner
Andre
A
Thomson
Angus W
AW
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D021122:Protein Subunits / Q000096:biosynthesis; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis / Q000502:physiology; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D021122:Protein Subunits; D019948:Receptors, Interleukin-4; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus