TY - JOUR
T1 - IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells
AU - Guenova, Emmanuella
AU - Skabytska, Yuliya
AU - Hoetzenecker, Wolfram
AU - Weindl, Günther
AU - Sauer, Karin
AU - Tham, Manuela
AU - Kim, Kyu-Won
AU - Park, Ji-Hyeon
AU - Seo, Ji Hae
AU - Ignatova, Desislava
AU - Cozzio, Antonio
AU - Levesque, Mitchell P
AU - Volz, Thomas
AU - Köberle, Martin
AU - Kaesler, Susanne
AU - Thomas, Peter
AU - Mailhammer, Reinhard
AU - Ghoreschi, Kamran
AU - Schäkel, Knut
AU - Amarov, Boyko
AU - Eichner, Martin
AU - Schaller, Martin
AU - Clark, Rachael A
AU - Röcken, Martin
AU - Biedermann, Tilo
PY - 2015/2/17
Y1 - 2015/2/17
N2 - 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/TH1 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.
AB - 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/TH1 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.
KW - Antigen-Presenting Cells/immunology
KW - Gene Silencing
KW - Humans
KW - Inflammation/physiopathology
KW - Interleukin-23/genetics
KW - Interleukin-4/physiology
KW - Th17 Cells/immunology
UR - https://www.scopus.com/pages/publications/84923172388
U2 - 10.1073/pnas.1416922112
DO - 10.1073/pnas.1416922112
M3 - Article
C2 - 25646481
SN - 0027-8424
VL - 112
SP - 2163
EP - 2168
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 7
ER -