IL-4 abrogates T sub( H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 7; p. 2163
• Main Authors: Guenova, Emmanuella, Skabytska, Yuliya, Hoetzenecker, Wolfram, Weindl, Guenther, Sauer, Karin, Tham, Manuela, Kim, Kyu-Won, Park, Ji-Hyeon, Seo, Ji Hae, Ignatova, Desislava, Cozzio, Antonio, Levesque, Mitchell P, Volz, Thomas, Koberle, Martin, Kaesler, Susanne, Thomas, Peter, Mailhammer, Reinhard, Ghoreschi, Kamran, Schaekel, Knut, Amarov, Boyko, Eichner, Martin, Schaller, Martin, Clark, Rachael A, Rocken, Martin, Biedermann, Tilo
• Format: Journal Article
• Language: English
• Published: 01.02.2015
• ISSN: 0027-8424

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- gamma -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.