4.3 Article

Comprehensive analysis of TLR4-induced transcriptional responses in interleukin 4-primed mouse macrophages

Journal

IMMUNOBIOLOGY
Volume 215, Issue 9-10, Pages 780-787

Publisher

ELSEVIER GMBH, URBAN & FISCHER VERLAG
DOI: 10.1016/j.imbio.2010.05.032

Keywords

Alternative macrophage activation; Gene regulation; Toll-like receptor

Categories

Funding

  1. Deutsche Forschungsgemeinschaft [Re1310/8]

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Interferon (IFN)gamma and interleukin (IL)-4 are central regulators of T helper 1 (Th1) and T helper 2 (Th2) immune responses, respectively. Both cytokines have a major impact on macrophage phenotypes: IFN gamma-priming and subsequent TLR4 activation induces so-called classically activated macrophages that are characterized by pronounced pro-inflammatory responses, whereas IL-4-treated macrophages, commonly called alternatively activated, are known to develop enhanced capacity for endocytosis, antigen presentation and tissue repair and are generally considered anti-inflammatory. Considering IL-4 as priming rather than activating stimulus, we now compared the TLR4-dependent global gene activation program in IFN gamma- versus IL-4-pretreated mouse macrophages, which has rarely been studied so far. Although both cytokines frequently induced opposing effects on gene transcription, the subsequent activation of bone marrow-derived macrophages by lipopolysaccharide (LPS) produced a strong, priming-dependent pro-inflammatory response in both macrophage types. For example, the production of key pro-inflammatory cytokines IL-6 and IL-12 was significantly higher in IL-4- versus IFN gamma-primed macrophages and several cytokine genes, including 1119, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in alternatively primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFN gamma-priming was actually found to suppress LPS-induced gene expression in a Stat1-dependent manner. Our data suggest that IL-4-priming is not per se anti-inflammatory but generates a macrophage that is tissue protective but still capable of mounting a strong inflammatory response after TLR4-dependent activation. (C) 2010 Elsevier GmbH. All rights reserved.

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