1. Antileishmanial Drugs Modulate IL-12 Expression and Inflammasome Activation in Primary Human Cells
- Author
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Jérôme Estaquier, Sonia André, Jane MacDougall, Anabela Cordeiro-da-Silva, Mireille Laforge, Sarah Pemberton, Yasmina Fortier, Vasco Rodrigues, Biosynthèse des Signaux Peptidiques [IBPS] (IBPS-BIOSIPE), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Parasite Disease Group, Universidade do Porto-Instituto de Biologia Molecular e Celular (IBMC)-Instituto de Investigação e Inovação em Saúde, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Ciências Biológicas, Universidade do Porto, and Université Laval [Québec] (ULaval)
- Subjects
CD4-Positive T-Lymphocytes ,Inflammasomes ,[SDV]Life Sciences [q-bio] ,T cell ,Immunology ,CD8-Positive T-Lymphocytes ,Pharmacology ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Secretion ,Leishmaniasis ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Cell Proliferation ,Leishmania ,Miltefosine ,Antiparasitic Agents ,Chemistry ,Inflammasome ,Interleukin-12 ,Interleukin-10 ,3. Good health ,medicine.anatomical_structure ,Interleukin 12 ,Cytokines ,Signal Transduction ,030215 immunology ,Pentamidine ,medicine.drug - Abstract
Leishmaniases are neglected tropical diseases. The treatment of leishmaniasis relies exclusively on chemotherapy including amphotericin B (AmB), miltefosine (hexadecylphosphocholine), and pentamidine. Besides the fact that these molecules are harmful for patients, little is known about the impact of such antileishmanial drugs on primary human cells in relation to immune function. The present study demonstrates that all antileishmanial drugs inhibit CD4 and CD8 T cell proliferation at the doses that are not related to increased cell death. Our results highlight that antileishmanial drugs have an impact on monocytes by altering the expression of IL-12 induced by LPS, whereas only AmB induced IL-10 secretion; both cytokines are essential in regulating Th1 cell–mediated immunity. Interestingly, IL-12 and anti–IL-10 Abs improved T cell proliferation inhibited by AmB. Furthermore, our results show that in contrast to hexadecylphosphocholine and pentamidine, AmB induced gene expression of the inflammasome pathway. Thus, AmB induced IL-1β and IL-18 secretions, which are reduced by specific inhibitors of caspase activation (Q-VD) and NLRP3 activation (MCC950). Our results reveal previously underestimated effects of antileishmanial drugs on primary human cells.
- Published
- 2020