IL-4 Abrogates T(H)17 Cell-mediated Inflammation by Selective Silencing of IL-23 in Antigen-presenting Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Feb 4

PMID 25646481

Citations 72

Authors

Emmanuella Guenova

Yuliya Skabytska

Wolfram Hoetzenecker

Gunther Weindl

Karin Sauer

Manuela Tham

Kyu-Won Kim

Ji-Hyeon Park

Ji Hae Seo

Desislava Ignatova

Antonio Cozzio

Mitchell P Levesque

Thomas Volz

Martin Koberle

Susanne Kaesler

Peter Thomas

Reinhard Mailhammer

Kamran Ghoreschi

Knut Schakel

Boyko Amarov

Martin Eichner

Martin Schaller

Rachael A Clark

Martin Rocken

Tilo Biedermann

Affiliations

Soon will be listed here.

Abstract

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.

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