IL-4 abrogates T 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; pp. 2163 - 2168
• Main Authors: Guenova, Emmanuella, Skabytska, Yuliya, Hoetzenecker, Wolfram, Weindl, Günther, 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
• Format: Journal Article
• Language: English
• Published: 17.02.2015
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1416922112

Significance Interleukin 4 (IL-4) has been shown to be highly protective against delayed type hypersensitivity and organ-specific autoimmune and autoinflammatory reactions in mice and humans, but its mode of action has remained controversial and has failed to be explained solely by redirection of T H 1/T H 17 toward a T H 2-type immune response. Here we uncovered that IL-4 selectively suppresses IL-23 transcription and secretion by cells of the innate immune system. We further describe a previously unidentified therapeutic mode of action of IL-4 in T H 17-mediated inflammation, and a physiologically highly relevant approach to selectively target IL-23/T H 17-dependent inflammation while sparing IL-12 and T H 1 immune responses. 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/T H 1 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.