Comprehensive analysis of TLR4-induced transcriptional responses in interleukin 4-primed mouse macrophages.
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: IFNgamma-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 IFNgamma- 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 IFNgamma-primed macrophages and several cytokine genes, including Il19, Ccl17, Ccl22, Ccl24 and Cxcl5, were preferentially induced in "alternatively" primed and LPS activated mouse macrophages. In a subset of genes, including IL12a, IFNgamma-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.
El Chartouni
Carol
C
Department of Haematology and Oncology, University Hospital Regensburg, Regensburg, Germany.
Rehli
Michael
M
D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D004705:Endocytosis / Q000276:immunology; D020869:Gene Expression Profiling; D007114:Immunization; D007249:Inflammation; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000235:genetics; D058408:Th1-Th2 Balance; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology*
D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D051197:Toll-Like Receptor 4; D015847:Interleukin-4; D007371:Interferon-gamma