Publikation
IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells
Wissenschaftlicher Artikel/Review - 02.02.2015
Guenova Emmanuella, Kaesler Susanne, Thomas Peter, Mailhammer Reinhard, Ghoreschi Kamran, Schäkel Knut, Amarov Boyko, Eichner Martin, Schaller Martin, Clark Rachael A, Röcken Martin, Köberle Martin, Volz Thomas, Levesque Mitchell P, Skabytska Yuliya, Hoetzenecker Wolfram, Weindl Günther, Sauer Karin, Tham Manuela, Kim Kyu-Won, Park Ji-Hyeon, Seo Ji Hae, Desislava Ignatova, Cozzio Antonio, Biedermann Tilo
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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 T(H)1 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/T(H)17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/T(H)17 responses without blocking IL-12/T(H)1, selective IL-4-mediated IL-23/T(H)17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent T(H)1 responses.