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

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

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

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.

Original languageEnglish
Pages (from-to)2163-2168
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number7
DOIs
StatePublished - 17 Feb 2015

Fingerprint

Dive into the research topics of 'IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells'. Together they form a unique fingerprint.

Cite this