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

被引：150

作者：

Guenova, Emmanuella ^{[1
,6
,12
]}

Skabytska, Yuliya ^{[1
]}

Hoetzenecker, Wolfram ^{[1
,6
,12
]}

Weindl, Guenther ^{[1
,2
]}

Sauer, Karin ^{[1
]}

Tham, Manuela ^{[1
]}

Kim, Kyu-Won ^{[3
,4
]}

Park, Ji-Hyeon ^{[3
,4
]}

Seo, Ji Hae ^{[3
,4
,5
]}

Ignatova, Desislava ^{[6
]}

Cozzio, Antonio ^{[6
]}

Levesque, Mitchell P. ^{[6
]}

Volz, Thomas ^{[1
]}

Koeberle, Martin ^{[1
,13
]}

Kaesler, Susanne ^{[1
]}

Thomas, Peter ^{[7
]}

Mailhammer, Reinhard ^{[8
]}

Ghoreschi, Kamran ^{[1
]}

Schaekel, Knut ^{[9
]}

Amarov, Boyko ^{[10
]}

Eichner, Martin ^{[11
]}

Schaller, Martin ^{[1
]}

Clark, Rachael A. ^{[12
]}

Roecken, Martin ^{[1
]}

Biedermann, Tilo a ^{[1
,13
]}

机构：

[1] Univ Tubingen, Dept Dermatol, D-72076 Tubingen, Germany

[2] Free Univ Berlin, Dept Pharmacol & Toxicol, Inst Pharm, D-14195 Berlin, Germany

[3] Seoul Natl Univ, Coll Pharm, NeuroVasc Coordinat Res Ctr, Seoul 151742, South Korea

[4] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 151742, South Korea

[5] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul 151742, South Korea

[6] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland

[7] Univ Munich, Dept Dermatol & Allergol, D-80337 Munich, Germany

[8] German Res Ctr Environm Hlth, Inst Clin Mol Biol & Tumor Genet, Helmholtz Zentrum Munchen, D-81377 Munich, Germany

[9] Univ Heidelberg Hosp, Dept Dermatol, D-69115 Heidelberg, Germany

[10] Free Univ Berlin, Inst Stat & Econometr, D-14195 Berlin, Germany

[11] Univ Tubingen, Dept Med Biometry, D-72076 Tubingen, Germany

[12] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA

[13] Tech Univ Munich, Dept Dermatol & Allergy, D-80290 Munich, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 07期

关键词：

IL-4; T(H)17; IL-23; psoriasis; dendritic cells; DENDRITIC CELLS; TH2; RESPONSES; AUTOIMMUNE ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; INTERLEUKIN (IL)-4; PSORIASIS-VULGARIS; MURINE COLITIS; CYTOKINE; THERAPY; DISEASE;

D O I：

10.1073/pnas.1416922112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 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.

引用

页码：2163 / 2168

页数：6

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