Rapamycin induces a caspase-independent cell death in human monocytes

A. Mercalli, V. Sordi, M. Ponzoni, P. Maffi, F. De Taddeo, G. Gatti, P. Servida, M. Bernardi, L. Bellio, F. Bertuzzi, A. Secchi, E. Bonifacio, L. Piemonti

Research output: Contribution to journalArticle

Abstract

The immunosuppressive activity of rapamycin (RAPA) and its efficacy as an anti-rejection agent in organ transplantation have been ascribed principally to its anti-proliferative effects on T cells, while the activity on monocytes is partially unknown. In vitro, RAPA reduced monocyte survival by inducing a caspase-independent cell death. RAPA-induced monocyte cell death (RAPA-CD) was impeded by activation of granulocyte macrophage-colony stimulating factor family receptors or toll-like receptor 4, and by exposure to inflammatory cytokines. In vivo, in patients who received RAPA monotherapy as part of pre-conditioning for islet transplantation, RAPA affected survival of myeloid lineage cells. In the peripheral blood, CD33+ and CD14+ cells decreased, whereas lymphocytes appeared unaffected. In the bone marrow, myeloid precursors such as CD15+ and CD15+/CD16+ were selectively and significantly decreased, but no major cytotoxic effects were observed. The RAPA-CD suggests a dependence of monocytes on mammalian target of RAPA pathways for nutrient usage, and this feature implies that RAPA could be selectively useful as a treatment to reduce monocytes or myeloid cells in conditions where these cells negatively affect patient, suggesting a potential anti-inflammatory action of this drug.

Original languageEnglish
Pages (from-to)1331-1341
Number of pages11
JournalAmerican Journal of Transplantation
Volume6
Issue number6
DOIs
Publication statusPublished - Jun 2006

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Keywords

  • Apoptosis
  • Inflammation
  • Rapamycin

ASJC Scopus subject areas

  • Immunology

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