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


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.

Download full-text


Available from: Yaacov Barak,
    • "In contrast, tolerogenic DCs are characterized by a resistance to maturation along with the expression of immune-modulatory factors, which corresponds to an increased T regulatory cell (Treg) response (Pulendran et al., 2010). New data suggest that tolerogenic DCs display a high levels of fatty-acid oxidation and low levels of glycolysis reminiscent of the anti-inflammatory M2 macrophage (Cook et al., 2012; Ferreira et al., 2012; Szanto et al., 2010) DCs lacking PPAR-g show increased immunogenicity while simultaneously failing to induce tolerogenic T cell responses (Klotz et al., 2007), further promoting a link between fatty-acid oxidation and a suppressive immune phenotype. Future studies need to further explore how metabolism differs in different subsets of DCs, and whether alterations in metabolism specifically in these cells is necessary to activate the transcriptional networks that establish these subsets. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria are well appreciated for their role as biosynthetic and bioenergetic organelles. In the past two decades, mitochondria have emerged as signaling organelles that contribute critical decisions about cell proliferation, death, and differentiation. Mitochondria not only sustain immune cell phenotypes but also are necessary for establishing immune cell phenotype and their function. Mitochondria can rapidly switch from primarily being catabolic organelles generating ATP to anabolic organelles that generate both ATP and building blocks for macromolecule synthesis. This enables them to fulfill appropriate metabolic demands of different immune cells. Mitochondria have multiple mechanisms that allow them to activate signaling pathways in the cytosol including altering in AMP/ATP ratio, the release of ROS and TCA cycle metabolites, as well as the localization of immune regulatory proteins on the outer mitochondrial membrane. In this Review, we discuss the evidence and mechanisms that mitochondrial dependent signaling controls innate and adaptive immune responses. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 03/2015; 42(3-3):406-417. DOI:10.1016/j.immuni.2015.02.002 · 21.56 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
Show more