STAT6 Transcription Factor Is a Facilitator of the Nuclear Receptor PPARγ-Regulated Gene Expression in Macrophages and Dendritic Cells

Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Research Center for Molecular Medicine, Egyetem ter 1. Debrecen, H-4010, Hungary.
Immunity (Impact Factor: 21.56). 11/2010; 33(5):699-712. DOI: 10.1016/j.immuni.2010.11.009
Source: PubMed

ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) is a lipid-activated transcription factor regulating lipid metabolism and inflammatory response in macrophages and dendritic cells (DCs). These immune cells exposed to distinct inflammatory milieu show cell type specification as a result of altered gene expression. We demonstrate here a mechanism how inflammatory molecules modulate PPARγ signaling in distinct subsets of cells. Proinflammatory molecules inhibited whereas interleukin-4 (IL-4) stimulated PPARγ activity in macrophages and DCs. Furthermore, IL-4 signaling augmented PPARγ activity through an interaction between PPARγ and signal transducer and activators of transcription 6 (STAT6) on promoters of PPARγ target genes, including FABP4. Thus, STAT6 acts as a facilitating factor for PPARγ by promoting DNA binding and consequently increasing the number of regulated genes and the magnitude of responses. This interaction, underpinning cell type-specific responses, represents a unique way of controlling nuclear receptor signaling by inflammatory molecules in immune cells.

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Available from: Yaacov Barak, Sep 29, 2015
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    • "Furthermore, DCs conditioned by IL-4 acquire a phenotype highly reminiscent of alternatively activated (M2) macrophages and expression of M2-associated activation markers on DCs is required for optimal induction of IL-10-secreting T cells (24). The fact that M2 activation by IL-4 is dependent on increased fatty acid oxidation (FAO) and OXPHOS (25–27) makes it conceivable that there is a causal link between mitochondrial metabolism fueled by FAO and the acquisition of a tolerogenic phenotype by DCs. The observations that direct inhibition of glycolysis in TLR-activated DCs favors the induction of Foxp3-expressing Th cells at the expense of IFN-γ-producing Th1 cells (16), and that resveratrol and rosiglitazone, drugs known to promote FAO (28) and mitochondrial biogenesis (29), respectively, interfere with TLR-induced DC activation and can render them tolerogenic (30–33), would support this idea. "
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    ABSTRACT: Dendritic cells (DCs) are key regulators of both immunity and tolerance by controlling activation and polarization of effector T helper cell and regulatory T cell responses. Therefore, there is a major focus on developing approaches to manipulate DC function for immunotherapy. It is well known that changes in cellular activation are coupled to profound changes in cellular metabolism. Over the past decade there is a growing appreciation that these metabolic changes also underlie the capacity of immune cells to perform particular functions. This has led to the concept that the manipulation of cellular metabolism can be used to shape innate and adaptive immune responses. While most of our understanding in this area has been gained from studies with T cells and macrophages, evidence is emerging that the activation and function of DCs are also dictated by the type of metabolism these cells commit to. We here discuss these new insights and explore whether targeting of metabolic pathways in DCs could hold promise as a novel approach to manipulate the functional properties of DCs for clinical purposes.
    Frontiers in Immunology 05/2014; 5:203. DOI:10.3389/fimmu.2014.00203
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    • "PPAR-γ seems to be of particular importance to alternative macrophage activation, as its expression is induced by IL-4 (Huang et al., 1999). It has subsequently been shown that signal transducer and activator of transcription 6 (STAT6), the downstream transcription factor of IL-4 signaling, physically interacts with PPAR-γ at transcriptionally important regions of M2 signature genes to augment their expression (Szanto et al., 2010). Macrophage-specific PPAR-γ knockout mice have also been shown to have an attenuated M2 phenotype: the expression of M2 signature genes such as Arg1 were blunted, which was coupled with a reduced fatty acid oxidative metabolism (Odegaard et al., 2007). "
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    ABSTRACT: Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism as well as salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5]) expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders.
    Frontiers in Physiology 05/2014; 5:146. DOI:10.3389/fphys.2014.00146 · 3.53 Impact Factor
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    • "STAT6 is a regulator of PPARγ response; IL-4 induces augmented PPARγ activity through a STAT6-dependent mechanism [11,27]. To identify the role of STAT6 on PPARγ activation induced by IL-4 and RvD1, we used leflunomide (an inhibitor suppressing tyrosine phosphorylation of STAT6 and preventing subsequent DNA binding) and GW9662 (a PPARγ antagonist) [26,28]. "
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    ABSTRACT: Microglia play key roles in innate immunity, homeostasis, and neurotropic support in the central nervous system. Similar to macrophages, microglia adopt two different activation phenotypes, the classical and alternative activation. Resolvin D1 (RvD1) is considered to display potent anti-inflammatory and pro-resolving actions in inflammatory models. In this present study, we investigate the effect of RvD1 on IL-4-induced alternative activation in murine BV-2 microglial cells. BV-2 cells were incubated with RvD1 alone, IL-4 alone, or the combination of RvD1 and IL-4. Western blot and immunofluorescence were performed to detect protein levels of alternative activation markers arginase 1 (Arg1), chitinase 3-like 3 (Ym1). Moreover, we investigated the effects of RvD1 on IL-4-induced activation of signal transducer and activators of transcription 6 (STAT6) and peroxisome proliferator-activated receptor gamma (PPARgamma). RvD1 promoted IL-4-induced microglia alternative activation by increasing the expression of Arg1 and Ym1. RvD1 also enhanced phosphorylation of STAT6, nuclear translocation of PPARgamma and the DNA binding activity of STAT6 and PPARgamma. These effects were reversed by butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (a formyl peptide receptor 2 antagonist). Further, the effects of RvD1 and IL-4 on Arg1 and Ym1 were blocked by the application of leflunomide (a STAT6 inhibitor) or GW9662 (a PPARgamma antagonist). Our studies demonstrate that RvD1 promotes IL-4-induced alternative activation via STAT6 and PPARgamma signaling pathways in microglia. These findings suggest that RvD1 may have therapeutic potential for neuroinflammatory diseases.
    Journal of Neuroinflammation 04/2014; 11(1):72. DOI:10.1186/1742-2094-11-72 · 5.41 Impact Factor
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