Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production

Sibylle Von Vietinghoff, Hui Ouyang, Klaus Ley

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Mycophenolic acid is a commonly used immunosuppressant after organ transplantation and in autoimmune diseases; however, myelosuppression is a major complication despite its largely favorable side-effect profile. Mycophenolic acid targets inosine monophosphate dehydrogenase, which is essential for T-cell proliferation. The T-cell cytokine interleukin-17 (IL-17 or IL-17A) and its receptor maintain normal neutrophilic granulocyte numbers in mice by induction of granulocyte-colony-stimulating factor. To test whether mycophenolic acid induces neutropenia by inhibiting IL-17-producing T cells, we treated C57Bl/6 mice with mycophenolate-mofetil (the orally available pro-drug) and found a dose-dependent decrease in blood neutrophils. This myelosuppressive effect was completely abolished in mice that lack the IL-17 receptor. Mycophenolic acid delayed myeloid recovery after bone marrow transplantation and decreased the percentage of IL-17-producing T cells in the spleen and thymus, and inhibited IL-17 production in human and mouse T cells in vitro. Injection of IL-17 during mycophenolic acid treatment overcame the suppression of the circulating neutrophil levels. Our study shows that mycophenolic acid suppresses neutrophil production by inhibiting IL-17 expression, suggesting that measurement of this interleukin might be useful in estimating the risk of neutropenia in clinical settings.

Original languageEnglish (US)
Pages (from-to)79-88
Number of pages10
JournalKidney International
Volume78
Issue number1
DOIs
StatePublished - Jul 2010
Externally publishedYes

Keywords

  • IL-17
  • Inosine-monophosphate dehydrogenase
  • Mycophenolate
  • Neutropenia

ASJC Scopus subject areas

  • Nephrology

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