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* Université de Bordeaux-2, Bordeaux, France;
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5164, Bordeaux, France;
Institut Fédératif de Recherche 66, Bordeaux, France;
Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France;
¶ Department de Pharmacologie Clinique et Toxicologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France;
|| Institut National de la Santé et de la Recherche Médicale Unité 657, Bordeaux, France;
# Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5095, Bordeaux, France
Mycophenolate mofetil (MMF) is an immunosuppressive agent used in transplantation. Over the last decade, MMF has also emerged as an alternative therapeutic regimen for autoimmune diseases, mainly for patients refractory to other therapies. The active compound of MMF, mycophenolic acid (MPA), depletes the intracellular pool of guanosine tri-phosphate through inosine monophosphate dehydrogenase blockade. The molecular mechanism involved in the elimination of T and B lymphocytes upon inhibition of inosine monophosphate dehydrogenase remains elusive. In this study, we showed that in contrast to the immunosuppressors azathioprine, cyclosporin A, and tacrolimus, MPA killed lymphocytes through the activation of a caspase-independent necrotic signal. Furthermore, the MPA-mediated necrotic signal relied on the transmission of a novel intracellular signal involving Rho-GTPase Cdc42 activity and actin polymerization. In addition to its medical interest, this study sheds light on a novel and atypical molecular mechanism leading to necrotic cell death.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Association pour la Recherche sur le Cancer (Grant 3798), Fondation de France, Agence Nationale de Recherches (Grant JC07_183182), Ligue Contre le Cancer (Comité de la Dordogne), and Agence de Biomédecine. P.L. is employed by Institut National de la Santé et de la Recherche Médicale. B.C.D. is supported by the Fondation de France (Postdoctoral Fellowship in Leukemia).
2 B.C.-D. and G.G. share common authorship.
3 Address correspondence and reprint requests to Dr. Patrick Legembre, Université de Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux, France. E-mail address: patrick.legembre{at}inserm.fr
4 Abbreviations used in this paper: IMPDH, inosine 5'-monophosphate dehydrogenase; CytD, cytochalasin D; FADD, Fas-associated death domain protein; LC3, L chain 3; LtnA, latrunculin A; MMF, mycophenolate mofetil; MNNG, N-methyl-N'-nitro-N'-nitrosoguanidine; MPA, mycophenolic acid; pNA, p-nitroanilide; RIP, receptor-interacting protein; SLE, systemic lupus erythematosus; zVAD-fmk, N-benzyloxycarbonyl valine-alanine-aspartate-fluoromethylketone.
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