Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo

Holger Hackstein, Timucin Taner, Alan F. Zahorchak, Adrian E. Morelli, Alison J. Logar, Andre Gessner, Angus W. Thomson

Research output: Contribution to journalArticle

289 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4457-4463
Number of pages7
JournalBlood
Volume101
Issue number11
DOIs
StatePublished - Jun 1 2003
Externally publishedYes

Fingerprint

Sirolimus
Interleukin-4
Dendritic Cells
T-cells
Interleukin-4 Receptors
Tacrolimus Binding Proteins
T-Lymphocytes
Transplants
Lymphocytes
Macrolides
Graft Rejection
Hematologic Neoplasms
Immunosuppressive Agents
In Vitro Techniques
Autoimmune Diseases
Interleukin-2
Intercellular Signaling Peptides and Proteins
Bone
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Hackstein, H., Taner, T., Zahorchak, A. F., Morelli, A. E., Logar, A. J., Gessner, A., & Thomson, A. W. (2003). Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood, 101(11), 4457-4463. https://doi.org/10.1182/blood-2002-11-3370

Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. / Hackstein, Holger; Taner, Timucin; Zahorchak, Alan F.; Morelli, Adrian E.; Logar, Alison J.; Gessner, Andre; Thomson, Angus W.

In: Blood, Vol. 101, No. 11, 01.06.2003, p. 4457-4463.

Research output: Contribution to journalArticle

Hackstein, H, Taner, T, Zahorchak, AF, Morelli, AE, Logar, AJ, Gessner, A & Thomson, AW 2003, 'Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo', Blood, vol. 101, no. 11, pp. 4457-4463. https://doi.org/10.1182/blood-2002-11-3370
Hackstein, Holger ; Taner, Timucin ; Zahorchak, Alan F. ; Morelli, Adrian E. ; Logar, Alison J. ; Gessner, Andre ; Thomson, Angus W. / Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. In: Blood. 2003 ; Vol. 101, No. 11. pp. 4457-4463.
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