Mycophenolic acid suppresses granulopoiesis by inhibition of interleukin-17 production.
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.
von Vietinghoff
Sibylle
S
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA. sibylle@liai.org
Ouyang
Hui
H
Ley
Klaus
K
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003115:Colony-Stimulating Factors / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D019891:Leukopoiesis / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology*; D009503:Neutropenia / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D003115:Colony-Stimulating Factors; D016207:Cytokines; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D016179:Granulocyte Colony-Stimulating Factor; D009173:Mycophenolic Acid