Attila Szanto

Publications of Attila Szanto

• Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response.

  Authors: Laszlo Nagy, Attila Szanto, Istvan Szatmari, Lajos Széles

  Physiological reviews. 04/2012; 92(2):739-89.

  A key issue in the immune system is to generate specific cell types, often with opposing activities. The mechanisms of differentiation and subtype specification of immune cells such as macrophagesA key issue in the immune system is to generate specific cell types, often with opposing activities. The mechanisms of differentiation and subtype specification of immune cells such as macrophages and dendritic cells are critical to understand the regulatory principles and logic of the immune system. In addition to cytokines and pathogens, it is increasingly appreciated that lipid signaling also has a key role in differentiation and subtype specification. In this review we explore how intracellular lipid signaling via a set of transcription factors regulates cellular differentiation, subtype specification, and immune as well as metabolic homeostasis. We introduce macrophages and dendritic cells and then we focus on a group of transcription factors, nuclear receptors, which regulate gene expression upon receiving lipid signals. The receptors we cover are the ones with a recognized physiological function in these cell types and ones which heterodimerize with the retinoid X receptor. These are as follows: the receptor for a metabolite of vitamin A, retinoic acid: retinoic acid receptor (RAR), the vitamin D receptor (VDR), the fatty acid receptor: peroxisome proliferator-activated receptor γ (PPARγ), the oxysterol receptor liver X receptor (LXR), and their obligate heterodimeric partner, the retinoid X receptor (RXR). We discuss how they can get activated and how ligand is generated and eliminated in these cell types. We also explore how activation of a particular target gene contributes to biological functions and how the regulation of individual target genes adds up to the coordination of gene networks. It appears that RXR heterodimeric nuclear receptors provide these cells with a coordinated and interrelated network of transcriptional regulators for interpreting the lipid milieu and the metabolic changes to bring about gene expression changes leading to subtype and functional specification. We also show that these networks are implicated in various immune diseases and are amenable to therapeutic exploitation.

• Carboxypeptidase-M is regulated by lipids and CSFs in macrophages and dendritic cells and expressed selectively in tissue granulomas and foam cells.

  Authors: Ioannis Tsakiris, Daniel Torocsik, Adrienn Gyongyosi, Aniko Dozsa, Istvan Szatmari, Attila Szanto, Gyorgyike Soos, Zoltan Nemes, Laszlo Igali, Ildiko Marton, Zoltan Takats, Laszlo Nagy, Balazs Dezso

  Laboratory investigation; a journal of technical methods and pathology. 12/2011; 92(3):345-61.

  Granulomatous inflammations, characterized by the presence of activated macrophages (MAs) forming epithelioid cell (EPC) clusters, are usually easy to recognize. However, in ambiguous cases the useGranulomatous inflammations, characterized by the presence of activated macrophages (MAs) forming epithelioid cell (EPC) clusters, are usually easy to recognize. However, in ambiguous cases the use of a MA marker that expresses selectively in EPCs may be needed. Here, we report that carboxypeptidase-M (CPM), a MA-differentiation marker, is preferentially induced in EPCs of all granuloma types studied, but not in resting MAs. As CPM is not expressed constitutively in MAs, this allows utilization of CPM-immunohistochemistry in diagnostics of minute granuloma detection when dense non-granulomatous MAs are also present. Despite this rule, hardly any detectable CPM was found in advanced/active tubercle caseous disease, albeit in early tuberculosis granuloma, MAs still expressed CPM. Indeed, in vitro both the CPM-protein and -mRNA became downregulated when MAs were infected with live mycobacteria. In vitro, MA-CPM transcript is neither induced remarkably by interferon-γ, known to cause classical MA activation, nor by IL-4, an alternative MA activator. Instead, CPM is selectively expressed in lipid-laden MAs, including the foam cells of atherosclerotic plaques, xanthomatous lesions and lipid pneumonias. By using serum, rich in lipids, and low-density lipoprotein (LDL) or VLDL, CPM upregulation could be reproduced in vitro in monocyte-derived MAs both at transcriptional and protein levels, and the increase is repressed under lipid-depleted conditions. The microarray analyses support the notion that CPM induction correlates with a robust progressive increase in CPM gene expression during monocyte to MA maturation and dendritic cell (DC) differentiation mediated by granulocyte-MA-colony-stimulating factor+IL-4. M-CSF alone also induced CPM. These results collectively indicate that CPM upregulation in MAs is preferentially associated with increased lipid uptake, and exposure to CSF, features of EPCs, also. Therefore, CPM-immunohistochemistry is useful for granuloma and foam MA detections in tissue sections. Furthermore, the present data offer CPM for the first time to be a novel marker and cellular player in lipid uptake and/or metabolism of MAs by promoting foam cell formation.

• Voltage-gated sodium channel Nav1.7 maintains the membrane potential and regulates the activation and chemokine-induced migration of a monocyte-derived dendritic cell subset.

  Authors: Katalin Kis-Toth, Peter Hajdu, Ildiko Bacskai, Orsolya Szilagyi, Ferenc Papp, Attila Szanto, Edit Posta, Peter Gogolak, Gyorgy Panyi, Eva Rajnavolgyi

  Journal of immunology (Baltimore, Md. : 1950). 06/2011; 187(3):1273-80.

  Expression of CD1a protein defines a human dendritic cell (DC) subset with unique functional activities. We aimed to study the expression of the Nav1.7 sodium channel and the functional consequencesExpression of CD1a protein defines a human dendritic cell (DC) subset with unique functional activities. We aimed to study the expression of the Nav1.7 sodium channel and the functional consequences of its activity in CD1a(-) and CD1a(+) DC. Single-cell electrophysiology (patch-clamp) and quantitative PCR experiments performed on sorted CD1a(-) and CD1a(+) immature DC (IDC) showed that the frequency of cells expressing Na(+) current, current density, and the relative expression of the SCN9A gene encoding Nav1.7 were significantly higher in CD1a(+) cells than in their CD1a(-) counterparts. The activity of Nav1.7 results in a depolarized resting membrane potential (-8.7 ± 1.5 mV) in CD1a(+) IDC as compared with CD1a(-) cells lacking Nav1.7 (-47 ± 6.2 mV). Stimulation of DC by inflammatory signals or by increased intracellular Ca(2+) levels resulted in reduced Nav1.7 expression. Silencing of the SCN9A gene shifted the membrane potential to a hyperpolarizing direction in CD1a(+) IDC, resulting in decreased cell migration, whereas pharmacological inhibition of Nav1.7 by tetrodotoxin sensitized the cells for activation signals. Fine-tuning of IDC functions by a voltage-gated sodium channel emerges as a new regulatory mechanism modulating the migration and cytokine responses of these DC subsets.

• Cytosolic DNA-activated human dendritic cells are potent activators of the adaptive immune response.

  Authors: Katalin Kis-Toth, Attila Szanto, To-Ha Thai, George C Tsokos

  Journal of immunology (Baltimore, Md. : 1950). 06/2011; 187(3):1222-34.

  Recent studies in cell lines and genetically engineered mice have demonstrated that cytosolic dsDNA could activate dendritic cells (DCs) to become effector APCs. Recognition of DNA might be a majorRecent studies in cell lines and genetically engineered mice have demonstrated that cytosolic dsDNA could activate dendritic cells (DCs) to become effector APCs. Recognition of DNA might be a major factor in antimicrobial immune responses against cytosolic pathogens and also in human autoimmune diseases such as systemic lupus erythematosus. However, the role of cytosolic dsDNA in human DC activation and its effects on effector T and B cells are still elusive. In this study, we demonstrate that intracellular dsDNA is a potent activator of human monocyte-derived DCs as well as primary DCs. Activation by dsDNA depends on NF-κB activation, partially on the adaptor molecule IFN-promoter stimulator-1 and the novel cytosolic dsDNA receptor IFI16, but not on the previously recognized dsDNA sentinels absent in melanoma 2, DNA-dependent activator of IFN regulatory factor 3, RNA polymerase III, or high-mobility group boxes. More importantly, we report for the first time, to our knowledge, that human dsDNA-activated DCs, rather than LPS- or inflammatory cytokine mixture-activated DCs, represent the most potent inducers of naive CD4(+) T cells to promote Th1-type cytokine production and generate CD4(+) and CD8(+) cytotoxic T cells. dsDNA-DCs, but not LPS- or mixture-activated DCs, induce B cells to produce complement-fixing IgG1 and IgG3 Abs. We propose that cytosolic dsDNA represents a novel, more effective approach to generate DCs to enhance vaccine effectiveness in reprogramming the adaptive immune system to eradicate infectious agents, autoimmunity, allergy, and cancer.

• Chronic obstructive pulmonary disease-specific gene expression signatures of alveolar macrophages as well as peripheral blood monocytes overlap and correlate with lung function.

  Authors: Szilard Poliska, Eszter Csanky, Attila Szanto, Istvan Szatmari, Bertalan Mesko, Lajos Szeles, Balazs Dezso, Beata Scholtz, Janos Podani, Iain Kilty, Laszlo Takacs, Laszlo Nagy

  Respiration; international review of thoracic diseases. 03/2011; 81(6):499-510.

  Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by progressive airflow limitation and significant extrapulmonary (systemic) effects that lead to co-morbidChronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by progressive airflow limitation and significant extrapulmonary (systemic) effects that lead to co-morbid conditions, though the pathomechanism of COPD is largely undetermined. Alveolar macrophages (AM) derived from peripheral monocytes (MO) appear to play a key role in initiating and/or sustaining disease progression. To identify disease- and cell type-specific gene expression profiles and potential overlaps in those in order to diagnose COPD, characterize its progression and determine the effect of drug treatment. Global gene expression analysis was used for primary screening in order to obtain expression signatures of AMs and circulating MOs of COPD patients and healthy controls. The results of microarray analyses of AMs (20 controls and 26 COPD patients) and MOs (16 controls and 22 COPD patients) were confirmed and validated by real-time quantitative polymerase chain reaction. We have identified gene sets specifically associated with COPD in AMs and MOs. There were overlapping genes between the two cell types. Our data also show that COPD-specific gene expression signatures in AMs and MOs correlate with percent of predicted FEV(1). Disease-specific and overlapping gene expression signatures can be defined in lung-derived macrophages and also in circulating monocytes. Some of the validated expression changes in both cell types correlate with lung function and therefore could serve as biomarkers of disease progression.

• Differentially expressed genes associated with human limbal epithelial phenotypes: new molecules that potentially facilitate selection of stem cell-enriched populations.

  Authors: Lili Takács, Eniko Tóth, Gergely Losonczy, Attila Szanto, Tomi Bähr-Ivacevic, Vladimir Benes, András Berta, György Vereb

  Investigative ophthalmology & visual science. 11/2010; 52(3):1252-60.

  The aim of this study was to identify differentially expressed genes in the human limbal epithelium by microarray analysis. Total RNA isolates of human limbal and central corneal epithelia were usedThe aim of this study was to identify differentially expressed genes in the human limbal epithelium by microarray analysis. Total RNA isolates of human limbal and central corneal epithelia were used after transcription for hybridization on whole human genome expression microarrays. A set of differentially expressed genes detected by both microarrays was established. In the case of eight selected molecules, microarray results were confirmed by qRT-PCR, and protein expression in the cornea was examined by confocal immunofluorescence microscopy. Colocalization with the putative stem cell marker C/EBPδ was also examined. The authors established a database of 126 limbal overexpressed genes. qRT-PCR confirmed microarray results in all examined cases (SPON1, IFITM1, ITM2A, PHLDA1, CXCR4, FZD7, DCT, DKK4). Limbal localization of the protein product of SPON1, IFITM1, ITM2A, CXCR4, and DKK4 was shown with confocal immunofluorescence microscopy. SPON1, IFITM1, and ITM2A signals mostly colocalized with C/EBPδ-positive putative resting limbal stem cells. By detecting several new differentially expressed genes in the human corneal limbus, this study further expands current knowledge on the molecular signature of limbal epithelial stem cells. Plasma membrane localization of IFITM1 and ITM2A suggests their potential usefulness as targets to select stem cell-enriched populations from the limbal epithelium.

• STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells.

  Authors: Attila Szanto, Balint L Balint, Zsuzsanna S Nagy, Endre Barta, Balazs Dezso, Attila Pap, Lajos Szeles, Szilard Poliska, Melinda Oros, Ronald M Evans, Yaacov Barak, John Schwabe, Laszlo Nagy

  Immunity. 11/2010; 33(5):699-712.

  Peroxisome proliferator-activated receptor γ (PPARγ) is a lipid-activated transcription factor regulating lipid metabolism and inflammatory response in macrophages and dendritic cells (DCs). ThesePeroxisome 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.

• Research resource: transcriptome profiling of genes regulated by RXR and its permissive and nonpermissive partners in differentiating monocyte-derived dendritic cells.

  Authors: Lajos Széles, Szilárd Póliska, Gergely Nagy, Istvan Szatmari, Attila Szanto, Attila Pap, Malin Lindstedt, Saskia J A M Santegoets, Ralph Rühl, Balázs Dezsö, László Nagy

  Molecular endocrinology (Baltimore, Md.). 11/2010; 24(11):2218-31.

  Retinoid X receptors (RXRs) are heterodimerization partners for many nuclear receptors and also act as homodimers. Heterodimers formed by RXR and a nonpermissive partner, e.g. retinoic acid receptorRetinoid X receptors (RXRs) are heterodimerization partners for many nuclear receptors and also act as homodimers. Heterodimers formed by RXR and a nonpermissive partner, e.g. retinoic acid receptor (RAR) and vitamin D receptor (VDR), can be activated only by the agonist of the partner receptor. In contrast, heterodimers that contain permissive partners, e.g. liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR), can be activated by agonists for either the partner receptor or RXR, raising the possibility of pleiotropic RXR signaling. However, it is not known to what extent the receptor's activation results in triggering mechanisms dependent or independent of permissive heterodimers. In this study, we systematically and quantitatively characterized all probable RXR-signaling pathways in differentiating human monocyte-derived dendritic cells (Mo-DCs). Using pharmacological, microarray and quantitative RT-PCR techniques, we identified and characterized gene sets regulated by RXR agonists (LG100268 and 9-cis retinoic acid) and agonists for LXRs, PPARs, RARα, and VDR. Our results demonstrated that permissiveness was partially impaired in Mo-DCs, because a large number of genes regulated by PPAR or LXR agonists was not affected by RXR-specific agonists or was regulated to a lesser extent. As expected, we found that RXR agonists regulated only small portions of RARα or VDR targets. Importantly, we could identify and characterize PPAR- and LXR-independent pathways in Mo-DCs most likely mediated by RXR homodimers. These data suggested that RXR signaling in Mo-DCs was mediated via multiple permissive heterodimers and also by mechanism(s) independent of permissive heterodimers, and it was controlled in a cell-type and gene-specific manner.

• Structural basis for the activation of PPARgamma by oxidized fatty acids.

  Authors: Toshimasa Itoh, Louise Fairall, Kush Amin, Yuka Inaba, Attila Szanto, Balint L Balint, Laszlo Nagy, Keiko Yamamoto, John W R Schwabe

  Nature structural & molecular biology. 10/2008; 15(9):924-31.

  The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metabolism.The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metabolism. Although synthetic agonists for PPARgamma are widely used as insulin sensitizers, the identity of the natural ligand(s) for PPARgamma is still not clear. Suggested natural ligands include 15-deoxy-delta12,14-prostaglandin J2 and oxidized fatty acids such as 9-HODE and 13-HODE. Crystal structures of PPARgamma have revealed the mode of recognition for synthetic compounds. Here we report structures of PPARgamma bound to oxidized fatty acids that are likely to be natural ligands for this receptor. These structures reveal that the receptor can (i) simultaneously bind two fatty acids and (ii) couple covalently with conjugated oxo fatty acids. Thermal stability and gene expression analyses suggest that such covalent ligands are particularly effective activators of PPARgamma and thus may serve as potent and biologically relevant ligands.

• The many faces of PPARgamma: Anti-inflammatory by any means?

  Authors: Attila Szanto, Laszlo Nagy

  Immunobiology. 02/2008; 213(9-10):789-803.

  The peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily, a group of transcription factors that regulate expression of their target genes uponThe peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily, a group of transcription factors that regulate expression of their target genes upon ligand binding. As endogenous ligands, oxidized fatty acids and prostanoids can bind to and activate the receptor. Natural and synthetic PPARgamma activators have been studied extensively in many inflammatory settings and in most instances they have been shown to be anti-inflammatory. In this review we give an overview of the different molecular mechanisms how PPARgamma and its agonists exert their anti-inflammatory effects both at the cellular level and the level of the organism. The action of PPARgamma in acute and chronic inflammatory diseases and disease models will be presented.

• Nuclear receptors in macrophages: a link between metabolism and inflammation.

  Authors: Attila Szanto, Tamás Roszer

  FEBS letters. 02/2008; 582(1):106-16.

  Subclinical inflammation is a candidate etiological factor in the pathogenesis of metabolic syndrome and in the progression of atherosclerosis. A central role for activated macrophages has beenSubclinical inflammation is a candidate etiological factor in the pathogenesis of metabolic syndrome and in the progression of atherosclerosis. A central role for activated macrophages has been elucidated recently as important regulators of the inflammatory process in atherosclerosis. Macrophage differentiation and function can be modulated by a class of transcription factors termed nuclear receptors. These are activated by intermediary products of basic metabolic processes. In this review the contribution of peroxisome proliferator-activated receptors and liver X receptors to macrophage functions in inflammation and lipid metabolism will be discussed in light of their roles in macrophages during atherosclerosis. In the past decade much effort has been made to understand the mechanisms how lipids are handled by macrophages and how inflammation could promote the atherogenic process. Here, we also provide an overview of these two fields.

• Roles for lipid-activated transcription factors in atherosclerosis.

  Authors: Laszlo Nagy, Attila Szanto

  Molecular nutrition & food research. 12/2005; 49(11):1072-4.

  The initial cellular event in atherosclerosis is the recruitment of monocytes to the vessel wall, and the formation of foam cells by the uptake of modified lipoproteins. The role of macrophages inThe initial cellular event in atherosclerosis is the recruitment of monocytes to the vessel wall, and the formation of foam cells by the uptake of modified lipoproteins. The role of macrophages in this process is the uptake and processing of lipoproteins ultimately leading to foam cell formation. These cells also sustain a chronic inflammatory reaction believed to participate in disease progression. We have been interested in identifying regulatory processes contributing to these events. Some members of a distinct class of transcription factors, nuclear hormone receptors, are expressed in macrophages and are likely to have roles in the initiation of atherosclerosis. We review here the identification of interrelated nuclear receptor-regulated pathways involving peroxisome proliferator-activated receptor, liver X receptor, and retinoid receptors, and contributing to lipid uptake and efflux in macrophages.

• Coagulation factor XIII-A. A flow cytometric intracellular marker in the classification of acute myeloid leukemias.

  Authors: János Kappelmayer, Agnes Simon, Eva Katona, Attila Szanto, László Nagy, Attila Kiss, Csongor Kiss, László Muszbek

  Thrombosis and haemostasis. 08/2005; 94(2):454-9.

  The association of coagulation factors with leukocytes have been demonstrated in several previous studies. This study was designed to study the sensitivity and specificity of factor XIII subunit AThe association of coagulation factors with leukocytes have been demonstrated in several previous studies. This study was designed to study the sensitivity and specificity of factor XIII subunit A (FXIII-A) labelling in cultured myeloblastic and monoblastic cell lines and to investigate the intracytoplasmic expression of FXIII-A in de novo acute myeloid leukemia (AML) samples. Myeloblastic and a monoblastic cell lines were cultured and investigated for lineage specific maturation markers and FXIII-A expression. Furthermore, FXIII-A expression was investigated in 12 normal samples (7 bone marrow and 5 peripheral blood), 86 de novo AML samples and 6 chronic myelomonocytic leukemia (CMML) samples. In the monoblastic MonoMac6 cell line the appearance of FXIII-A preceded that of CD14 while it remained negative in the myeloblastic PLB-985 cell line throughout its maturation period. Among the AML samples the average frequency of FXIII-A positive cells in myeloblastic leukemia samples was below 10%, while in M4 and M5AML samples it was above 50% and was significantly higher than the generally used CD14 marker (p < 0.0001). In the AML M4 and M5 cases, FXIII-A proved sensitive for the identification of monoblasts. FXIII-A can be considered as a reliable intracytoplasmic marker for the monocytic and megakaryocytic series and its presence is highly predictive for mono- and megakaryocytic AML and for CMML.

• Arginine methylation provides epigenetic transcription memory for retinoid-induced differentiation in myeloid cells.

  Authors: Balint L Balint, Attila Szanto, Andras Madi, Uta-Maria Bauer, Petra Gabor, Szilvia Benko, Laszlo G Puskás, Peter J A Davies, Laszlo Nagy

  Molecular and cellular biology. 08/2005; 25(13):5648-63.

  Cellular differentiation is governed by changes in gene expression, but at the same time, a cell's identity needs to be maintained through multiple cell divisions during maturation. In myeloid cellCellular differentiation is governed by changes in gene expression, but at the same time, a cell's identity needs to be maintained through multiple cell divisions during maturation. In myeloid cell lines, retinoids induce gene expression and a well-characterized two-step lineage-specific differentiation. To identify mechanisms that contribute to cellular transcriptional memory, we analyzed the epigenetic changes taking place on regulatory regions of tissue transglutaminase, a gene whose expression is tightly linked to retinoid-induced differentiation. Here we report that the induction of an intermediary or "primed" state of myeloid differentiation is associated with increased H4 arginine 3 and decreased H3 lysine 4 methylation. These modifications occur before transcription and appear to prime the chromatin for subsequent hormone-regulated transcription. Moreover, inhibition of methyltransferase activity, pre-acetylation, or activation of the enzyme PAD4 attenuated retinoid-regulated gene expression, while overexpression of PRMT1, a methyltransferase, enhanced retinoid responsiveness. Taken together, our results suggest that H4 arginine 3 methylation is a bona fide positive epigenetic marker and regulator of transcriptional responsiveness as well as a signal integration mechanism during cell differentiation and, as such, may provide epigenetic memory.

• Retinoids potentiate peroxisome proliferator-activated receptor gamma action in differentiation, gene expression, and lipid metabolic processes in developing myeloid cells.

  Authors: Attila Szanto, Laszlo Nagy

  Molecular pharmacology. 07/2005; 67(6):1935-43.

  Nuclear hormone receptors have been shown to be important transcription factors for regulating lipid metabolism in myeloid cells and were also implicated in differentiation processes of the myeloidNuclear hormone receptors have been shown to be important transcription factors for regulating lipid metabolism in myeloid cells and were also implicated in differentiation processes of the myeloid lineage and macrophages. Peroxisome proliferator-activated receptor gamma (PPARgamma) seems to be a key component of lipid uptake by inducing the scavenger receptor CD36 that mediates oxidized low-density lipoprotein uptake in macrophages. Retinoic acid receptors, on the other hand, were also shown to play important roles in myeloid cell differentiation. In this study, we present evidence for a cross-talk between these two nuclear receptor pathways in myeloid cells. We show that expression level of PPARgamma increases with the degree of monocyte/macrophage commitment during maturation. Activation of PPARgamma leads to the increased expression of maturation markers (e.g., CD14, CD36). It is interesting that retinoid treatment potentiates PPARgamma's ability to induce transcription of its target genes. Retinoid-increased PPARgamma response is sufficient for enhancing lipid uptake. Our data, taken together, indicate that the expression level of PPARgamma increases during monocyte/macrophage development. PPARgamma activity can be enhanced by retinoids at least in part via increasing PPARgamma expression level. These observations can be exploited to enhance therapeutically beneficial PPAR responses in myeloid cells.

• Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages.

  Authors: Attila Szanto, Szilvia Benko, Istvan Szatmari, Balint L Balint, Ibolya Furtos, Ralph Rühl, Sandor Molnar, Laszlo Csiba, Rita Garuti, Sebastiano Calandra, Hanna Larsson, Ulf Diczfalusy, Laszlo Nagy

  Molecular and cellular biology. 10/2004; 24(18):8154-66.

  Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptorCholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPARgamma, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPARgamma-, and LXR-regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPARgamma-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.

• The many faces of PPARγ: Anti-inflammatory by any means?

  Authors: Attila Szanto, Laszlo Nagy

  Immunobiology.

  The peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily, a group of transcription factors that regulate expression of their target genes upon ligandThe peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily, a group of transcription factors that regulate expression of their target genes upon ligand binding. As endogenous ligands, oxidized fatty acids and prostanoids can bind to and activate the receptor. Natural and synthetic PPARγ activators have been studied extensively in many inflammatory settings and in most instances they have been shown to be anti-inflammatory. In this review we give an overview of the different molecular mechanisms how PPARγ and its agonists exert their anti-inflammatory effects both at the cellular level and the level of the organism. The action of PPARγ in acute and chronic inflammatory diseases and disease models will be presented.

• Oxysterol signaling links cholesterol metabolism and inflammation via the liver X receptor in macrophages

  Authors: Dániel Töröcsik, Attila Szanto, László Nagy

  Molecular Aspects of Medicine.

  Sterols and fatty acids are common intermediary metabolites in all cells of the body. Oxidative modifications of these molecules can occur and result in the production of oxysterols and oxidizedSterols and fatty acids are common intermediary metabolites in all cells of the body. Oxidative modifications of these molecules can occur and result in the production of oxysterols and oxidized fatty acids. Significantly, these modified molecules not only participate in basic metabolic processes but they are also involved in signaling pathways. These two groups of molecules are known to regulate the activity of a special group of ligand-activated transcription factors, known as nuclear receptors. Oxysterols activate liver X receptor (LXR), while oxidized fatty acids regulate peroxisome proliferator-activated receptors (PPARs). These nuclear hormone receptors control the expression of their target genes upon ligand binding and via this effect many physiological as well as pathological processes. The role of the receptors and natural or synthetic activators have been studied extensively in the initiation, development and progression of atherosclerosis. Both the receptors themselves and their activators have been shown to exert anti-atherogenic effects. In this review we provide an overview of oxysterol-driven gene expression regulation. We introduce nuclear receptors, in particular LXR, how they become activated by oxysterols, how they work, what consequences of receptor activation on transcription regulation has and how these processes coordinate cholesterol metabolism and transport in macrophages. We place LXR into a network of transcription factors, enzymes and ligands. We also summarize data supporting the notion that LXR is also involved in the regulation of inflammatory processes. Finally, the in vivo consequences of LXR activation or deletion are discussed.