Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma

Bruns H, Büttner M, Fabri M, Mougiakakos D, Bittenbring JT, Hoffmann M, Beier F, Pasemann S, Jitschin R, Hofmann AD, Neumann F, Daniel C, Maurberger A, Kempkes B, Amann KU, Mackensen A, Gerbitz A (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 7

Pages Range: 282ra47

Journal Issue: 282

DOI: 10.1126/scitranslmed.aaa3230

Abstract

Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as Burkitt's lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. We show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D-treated M2 macrophages is cathelicidin-dependent. Finally, vitamin D treatment of 25-hydroxyvitamin D (25D)-deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor activity of TAMs and improves the efficacy of ADCC.

Authors with CRIS profile

Heiko Bruns Department of Medicine 5 – Haematology and Oncology Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie Markus Hoffmann Department of Medicine 3 – Rheumatology and Immunology Christoph Daniel Department of Nephropathology Anna Maurberger Professur für Hämatologie mit dem Schwerpunkt Zelluläre Immuntherapie Kerstin Ute Amann Professur für Nephropathologie Andreas Mackensen Lehrstuhl für Innere Medizin V

Involved external institutions

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Universität des Saarlandes (UdS) DE Germany (DE) Universität zu Köln DE Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE)

How to cite

APA:

Bruns, H., Büttner, M., Fabri, M., Mougiakakos, D., Bittenbring, J.T., Hoffmann, M.,... Gerbitz, A. (2015). Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma. Science Translational Medicine, 7(282), 282ra47. https://doi.org/10.1126/scitranslmed.aaa3230

MLA:

Bruns, Heiko, et al. "Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma." Science Translational Medicine 7.282 (2015): 282ra47.

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