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Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal homeostasis

https://doi.org/10.1016/j.cytogfr.2012.08.006Get rights and content

Abstract

Experiments in IL-15−/− and IL-15Rα−/− mice show that intra-renal IL-15, through IL-15Rα behaves as an epithelial survival factor. Recent data highlight new functions of IL-15 in renal homeostasis mediated by IL-15Rγ (CD132). Indeed, in CD132+ renal epithelial tubular cells IL-15 preserves E-cadherin expression inhibiting epithelial-mesenchymal transition (EMT). By contrast, during allograft rejection, the increased intra-graft IL-15 expression favors tubular destruction facilitating the intraepithelial recruitment of CD8 T cells expressing the E-cadherin ligand CD103. In renal cancer, loss of CD132 by epithelial cells defines a tumoral microenvironment where IL-15 triggers E-cadherin down-regulation and EMT. Finally, in CD132+ renal cancer stem cells IL-15 induces the generation of non-tumorigenic epithelial cells sensitive to cytotoxic drugs. These findings are discussed in the light of IL-15-based immunotherapy for renal cancer.

Section snippets

Interleukin-15 (IL-15): a cytokine of the IL-2 family

IL-15 was originally identified as a T-cell growth factor and natural killer (NK)-stimulating cytokine that binds to IL-2R components [1], [2]. The human IL-15 gene maps to chromosome 4 and is transcriptionally active in several normal cell types [1] including epithelial cells, monocytes, macrophages, dendritic cells (DCs), fibroblasts and some tumor cells [3]. However, IL-15 protein is produced in few cell types such as monocytes, macrophages [1], DCs [4] and stromal cells [5], suggesting that

Expression and functional role of IL-15 in epithelial cells

IL-15 is expressed in many non-immune cell types, suggesting potential functions of the cytokine outside the immune system. In this context, it has been shown that different types of epithelial cells produce IL-15 that not only integrates these cells into classical immune responses [53], [54], [55], [56], [57], [58], [59], [60] but also modifies their properties. Thus, keratinocytes produce IL-15 that modulates their survival, proliferation and cytokines secretion [25], [60], while enterocytes

Murine model

Data from IL-15−/− and IL-15Rα−/− mice highlight an obligate role for IL-15 and its receptor in the lymphopoiesis and in addition, reveals that IL-15 and IL-15Rα display an important role in kidney patho-physiology acting as survival factors for epithelial cells. In this context, IL-15 is atypical since it is constitutively and abundantly expressed and secreted by renal tubular epithelial cells (TECs) [58], behaving differently from the majority of the cytokines that are induced during

Human tubular renal epithelial cells (TECs)

Overall, the above mentioned results indicate that both IL-15 and its receptor are likely to have, in mice, an important role in both normal and pathological condition of the kidney, and several evidences suggest biological effects of IL-15 on human renal cells.

Different studies report the expression of IL-15Rα protein in human kidney that was detected in extracts of human renal tissue [64]. Subsequently, immunohistochemical studies showed that the IL-15Rβ chain is similarly expressed by cortex

Conclusions

Interleukin-15 is constitutively secreted by renal epithelial cells both in mice and humans and plays a major role in renal physiology behaving as an epithelial survival factor, preserving epithelial phenotype and function and possibly acting as an inducer of epithelial differentiation. IL-15 is produced as a soluble factor and/or in membrane-bound forms, likely mediating similar effects under both forms that could act in a complementary fashion. Increased or decreased expression of IL-15 and

Acknowledgements

The present study was made possible by grants from Agence de Biomedicine, Association pour la Recherche sur le Cancer (ARC), Fondation de France, NRB-Vaincre leCancer and AIRC (Italian Association for Cancer Research) IG 8915 and Compagnia di San Paolo. S.A. has a post-doctoral fellowship from ARC.

Julien Giron Michel obtained his Ph.D. degree with a project focused on the role of IL-15 in human hematopoiesis at the University Paris XI under the supervision of Professor Bruno Azzarone in the Inserm Unit 506. After a 3-year postdoctoral fellowship on the human natural killer cell receptors in the Immunology Laboratory at the Instituto Giannina Gaslini, Genoa Italy (Supervisor: doctor Roberto Biassoni), he got a staff scientist position at the French National Institute of Health and

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    Julien Giron Michel obtained his Ph.D. degree with a project focused on the role of IL-15 in human hematopoiesis at the University Paris XI under the supervision of Professor Bruno Azzarone in the Inserm Unit 506. After a 3-year postdoctoral fellowship on the human natural killer cell receptors in the Immunology Laboratory at the Instituto Giannina Gaslini, Genoa Italy (Supervisor: doctor Roberto Biassoni), he got a staff scientist position at the French National Institute of Health and Biomedical Research (INSERM) in the U-1014 Inserm (Villejuif, France) where he works on the expression and function of the IL-15/IL-15R system in kidney pathophysiology. 2003 Award of Paris Chancelleries for the best Ph.D. Thesis.

    Sandy Azzi obtained her Ph.D. degree with a project focused on the role of IL-15 in kidney cancer and the IL-15-induced epithelial differentiation of renal cancer stem cells at the University Paris XI (Supervisors: doctor Pierre Eid and doctor Julien Giron-Michel in the Inserm Unit 1014 Villejuif, France). At present, she has post doctoral position, working on Tumor microenvironment and vascular niche (Supervisor: doctor Julie Gavard at the Institut Cochin, Université Paris Descartes, Inserm Unit 1016, UMR-CNRS 8104, Paris, France. 2010 National Award of InCa (Institute National du Cancer) for the best project on renal cancer.

    Silvano Ferrini obtained his M.D. degree at the University of Genova in 1980. In 1983 he obtained a Specialty degree in Endocrinology by discussing a thesis on T cell subsets in autoimmune thyroid disorders. In 1983–1985 he completed his training in cellular immunology at the Ludwig Institute for Cancer Research, Lausanne, Switzerland, where he conducted studies on T cell cloning in ovarian cancer and identification of tumor-specific CTLs and on the phenotypic and functional characterization of NK and TCR gamma/delta-expressing T cell clones. In 1984 he obtained a Permanent position as research investigator at the Istituto Nazionale per la Ricerca sul Cancro in Genova. From 1995 he is teacher of Molecular Immunology at the Degree Course in Biotechnology, University of Genoa, Faculty of Medicine. In 2005 he became Head of the Laboratory of Immunotherapy at the same Institute. His actual research topics include studies on the role of cytokines and their receptors in human tumors and leukemias, preclinical studies of cancer vaccines, use of new combinational therapies using cytokines, genetically-modified tumor cells and antibodies in cancer immunotherapy.

    Dr. Salem Chouaib completed his undergraduate studies at the university of Pierre and Marie Curie (Paris VI) at Pasteur Institute. He received his Doctorat es-sciences (Ph.D.) in immunology (laboratory of Jean Dausset, Nobel prize in medicine) in 1983 from the same university. He then joined the Memorial Sloan Kettering Cancer Center in New York where he undertook a post-doctoral training in Human Immnogenetics Laboratory. In 1986, he was appointed as research associate at the French National Institute of Health and Biomedical Research (INSERM) and joined the Tumor Biology Department at the Institut Gustave Roussy. At present he is research director and is heading the INSERM research unit 753 (Human Cancer Immunology and Immunotherapy). Dr. Chouaib's laboratory currently focuses on the investigation of the functional cross talk between cytotoxic cells and tumor targets in the context of tumor microenvironment complexity and plasticity. Dr. Chouaib research was constantly directed at impulsing the transfer of fundamental concepts in clinical application in particular in the field of cancer vaccine and cancer immunotherapy. He was awarded the cancer research prize of the French ligue against cancer in 1992 and in 2004 the presidential prize in biotechnology. He is lecturing tumor immunology for the Ph.D. programs at the University Paris Sud. His research resulted in more than 220 scientific articles and several reviews in the field of human immunology and tumor biology as well as in editorship for contribution to several books. Furthermore he is guest lecturer at different universities. He is ad hoc referee for numerous journals and scientific foundations. He is a member of various professional associations and is scientific advisor and consultant in many scientific institutions.

    Dr. Camussi is currently President of the Course of Medical Biotechnology, Director of Ph.D. program in Medical Pathophysiology and Full Professor of Nephrology at the University of Torino, Italy. He has been appointed as Research Associate Professor in Microbiology and Pathology at the State University of New York at Buffalo (USA) and subsequently as Full Professor of Nephrology at the University of Naples, at the University of Pavia and as Director of the Department of Internal Medicine at the University of Torino. He is now the Head of a Stem Cell Laboratory at the Molecular Biotechnology Center and of the Laboratory of Vascular Biology and Angiogenesis at the Research Center for Experimental Medicine, University of Torino. He lists over 413 publications dealing on mediators of inflammation, renal immunopathology, neoangiogenesis, and stem cell biology. More recently he focused on the characterization of cancer stem cell in renal carcinoma and on the biological effects of stem cell-derived microvesicles.

    Pierre Eid studied biochemistry at the Louis Pasteur University of Strasbourg (France), where he got his Ph.D. in 1978 working on the aspartate semi-aldehyde dehydrogenase function (Supervisor Doctor Jean-François Biellman). After a two year postdoc working on the aspartate semi-aldehyde dehydrogenase active site sequencing (Supervisor Professor Hans Jornval, Karolinska Institute Stockholm, Sweden) and at the Institut Pasteur (Paris, France). Subsequently, he worked on Type I interferons, receptors and their signaling pathways until 2006 at the “Institut de Recherche Scientifique sur le Cancer” (Villejuif, France) where he got a staff scientist position at the French National Institute of Health and Biomedical Research (INSERM) becoming later Director of Research. Since 2007 he joined the B. Azzarone's group on Interleukin-15 in the renal physiopathology at the Inserm 1014 unit, Paul Brousse Hospital (Villejuif, France). His current interest is centered around the study of Interleukin-15 and the tumoral microenvironment in renal stem cells.

    Professor Bruno Azzarone obtained his M.D. degree at the Genoa University Italy, where he specialized in Virology becoming assistant Professor and subsequently associate Professor of Virology. After a 4-year postdoctoral fellowship at the U-50 Inserm in Villejuif France working on cell aging and cancer (Supervisor Doctor Macieira-Coelho), he got a staff scientist position at the French National Institute of Health and Biomedical Research (INSERM), becoming later Director of Research. He obtained his Ph.D. degree at the Faculty of Pharmacology Paris XI; with a project focused on the expression and function of IL-2/IL-2R system in human stromal and cancer cells (supervisor Professor Claude Jasmin). In 2001 he spent a sabbatical at the Pathology Institute of the University of Geneva, Suisse working with Professor Giulio Gabbiani on the contractile properties of vascular and respiratory smooth muscle cells. In 2002, he set up a research group at the U-1014 Inserm (Villejuif, France) to study the role of the IL-15/IL-15R system in human hematopoiesis and cancer.

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