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Guenova, E.* ; Skabytska, Y.* ; Hoetzenecker, W.* ; Weindl, G.* ; Sauer, K.* ; Tham, M.* ; Kim, K.W.* ; Park, J.H.* ; Seo, J.H.* ; Ignatova, D.* ; Cozzio, A.* ; Levesque, M.P.* ; Volz, T.* ; Köberle, M.* ; Kaesler, S.* ; Thomas, P.* ; Mailhammer, R. ; Ghoreschi, K.* ; Schäkel, K.* ; Amarov, B.* ; Eichner, M.* ; Schaller, M.* ; Clark, R.A.* ; Röcken, M.* ; Biedermann, T.*

IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells.

Proc. Natl. Acad. Sci. U.S.A. 112, 2163-2168 (2015)
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Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ-producing TH1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12-producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4-mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/TH17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/TH17 responses without blocking IL-12/TH1, selective IL-4-mediated IL-23/TH17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent TH1 responses.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Il-23 ; Il-4 ; Th17 ; Dendritic Cells ; Psoriasis; Dendritic Cells; Th2 Responses; Autoimmune Encephalomyelitis; Multiple-sclerosis; Interleukin (il)-4; Psoriasis-vulgaris; Murine Colitis; Cytokine; Therapy; Disease
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Journal Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Volume: 112, Issue: 7, Pages: 2163-2168 Article Number: , Supplement: ,
Publisher National Academy of Sciences
Publishing Place Washington
Reviewing status Peer reviewed
Institute(s) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-501400-001
PubMed ID 25646481
DOI 10.1073/pnas.1416922112
WOS ID WOS:000349446000078
Scopus ID 84923172388
Erfassungsdatum 2015-02-05
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