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Bruns, H.* ; Büttner, M.* ; Fabri, M.* ; Mougiakakos, D.* ; Bittenbring, J.T.* ; Hoffmann, M.H.* ; Beier, F.* ; Pasemann, S.* ; Jitschin, R.* ; Hofmann, A.D.* ; Neumann, F.J.* ; Daniel, C.* ; Maurberger, A.* ; Kempkes, B. ; Amann, K.* ; Mackensen, A.* ; Gerbitz, A.*

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

Sci. Transl. Med. 7:282ra47 (2015)
Verlagsversion DOI PMC
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Antimicrobial Peptide Ll-37; Non-hodgkins-lymphoma; Tumor-associated Macrophages; Bacillus-calmette-guerin; Human-monocytes; Monoclonal-antibody; Cancer Progression; Innate Immunity; D-receptor; Rituximab
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Zeitschrift Science Translational Medicine
Quellenangaben Band: 7, Heft: 282, Seiten: , Artikelnummer: 282ra47 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501500-002
PubMed ID 25855493
DOI 10.1126/scitranslmed.aaa3230
WOS ID WOS:000352535200004
Scopus ID 84927587443
Erfassungsdatum 2015-04-11
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