title: Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma.
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: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany. heiko.bruns@uk-erlangen.de.
authors: Heiko
authors: H
authors: Bruns
authors: Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Maike
authors: M
authors: Büttner
authors: Department of Dermatology and Center for Molecular Medicine, University of Cologne, 50937 Cologne, Germany.
authors: Mario
authors: M
authors: Fabri
authors: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Dimitrios
authors: D
authors: Mougiakakos
authors: Medizinische Klinik I, Saarland University Medical School, 66424 Homburg/Saar, Germany.
authors: Jörg T
authors: JT
authors: Bittenbring
authors: Department of Internal Medicine 3, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Markus H
authors: MH
authors: Hoffmann
authors: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Medical School, 52074 Aachen, Germany.
authors: Fabian
authors: F
authors: Beier
authors: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Shirin
authors: S
authors: Pasemann
authors: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Regina
authors: R
authors: Jitschin
authors: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Andreas D
authors: AD
authors: Hofmann
authors: Medizinische Klinik I, Saarland University Medical School, 66424 Homburg/Saar, Germany.
authors: Frank
authors: F
authors: Neumann
authors: Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Christoph
authors: C
authors: Daniel
authors: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Anna
authors: A
authors: Maurberger
authors: Department of Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Munich, Germany.
authors: Bettina
authors: B
authors: Kempkes
authors: Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Kerstin
authors: K
authors: Amann
authors: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Andreas
authors: A
authors: Mackensen
authors: Department of Internal Medicine 5-Hematology/Oncology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Armin
authors: A
authors: Gerbitz
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D054804:Cathelicidins