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

Author:

Guenova Emmanuella,Skabytska Yuliya,Hoetzenecker Wolfram,Weindl GüntherORCID,Sauer Karin,Tham Manuela,Kim Kyu-Won,Park Ji-Hyeon,Seo Ji Hae,Ignatova Desislava,Cozzio Antonio,Levesque Mitchell P.,Volz Thomas,Köberle Martin,Kaesler Susanne,Thomas Peter,Mailhammer Reinhard,Ghoreschi Kamran,Schäkel Knut,Amarov Boyko,Eichner Martin,Schaller Martin,Clark Rachael A.,Röcken Martin,Biedermann Tilo

Abstract

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.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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