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

• Verfasst von: Guenova, Emmanuella [VerfasserIn]
• Verfasst von: Schäkel, Knut [VerfasserIn]
• Titel: IL-4 abrogates TH17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells
• Verf.angabe: 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 Amarov, Martin Eichner, Martin Schaller, Rachael A. Clark, Martin Röcken, and Tilo Biedermann
• Umfang: 6 S.
• Fussnoten: Gesehen am 17.07.2017 ; Im Titel ist der Buchstabe "H" in TH17 tiefgestellt
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC): Proceedings of the National Academy of Sciences of the United States of America
• Jahr Quelle: 2015
• Band/Heft Quelle: 112(2015), 7, S. 2163-2168
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.1416922112
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1560915994

Abstract

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 TH1/TH17 toward a TH2-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 TH17-mediated inflammation, and a physiologically highly relevant approach to selectively target IL-23/TH17-dependent inflammation while sparing IL-12 and TH1 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 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.