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1.
PLoS One ; 12(5): e0176715, 2017.
Article in English | MEDLINE | ID: mdl-28493883

ABSTRACT

Bile acids are established signaling molecules next to their role in the intestinal emulsification and uptake of lipids. We here aimed to identify a potential interaction between bile acids and CD4+ Th cells, which are central in adaptive immune responses. We screened distinct bile acid species for their potency to affect T cell function. Primary human and mouse CD4+ Th cells as well as Jurkat T cells were used to gain insight into the mechanism underlying these effects. We found that unconjugated lithocholic acid (LCA) impedes Th1 activation as measured by i) decreased production of the Th1 cytokines IFNγ and TNFαα, ii) decreased expression of the Th1 genes T-box protein expressed in T cells (T-bet), Stat-1 and Stat4, and iii) decreased STAT1α/ß phosphorylation. Importantly, we observed that LCA impairs Th1 activation at physiological relevant concentrations. Profiling of MAPK signaling pathways in Jurkat T cells uncovered an inhibition of ERK-1/2 phosphorylation upon LCA exposure, which could provide an explanation for the impaired Th1 activation. LCA induces these effects via Vitamin D receptor (VDR) signaling since VDR RNA silencing abrogated these effects. These data reveal for the first time that LCA controls adaptive immunity via inhibition of Th1 activation. Many factors influence LCA levels, including bile acid-based drugs and gut microbiota. Our data may suggest that these factors also impact on adaptive immunity via a yet unrecognized LCA-Th cell axis.


Subject(s)
Adaptive Immunity/drug effects , Lithocholic Acid/pharmacology , Lymphocyte Activation/drug effects , Receptors, Calcitriol/metabolism , Th1 Cells/immunology , Animals , Bile Acids and Salts/metabolism , Cell Differentiation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation/drug effects , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Jurkat Cells , Mice, Inbred C57BL , Phosphorylation/drug effects , Th1 Cells/drug effects
2.
Biochem Soc Trans ; 42(2): 244-9, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24646225

ABSTRACT

TGR5 (Takeda G-protein-coupled receptor 5) [also known as GPBAR1 (G-protein-coupled bile acid receptor 1), M-BAR (membrane-type receptor for bile acids) or GPR131 (G-protein-coupled receptor 131)] is a G-protein-coupled receptor that was discovered as a bile acid receptor. TGR5 has specific roles in several tissues, among which are the regulation of energy expenditure, GLP-1 (glucagon-like peptide 1) secretion and gall bladder filling. An accumulating body of evidence now demonstrates that TGR5 also acts in a number of processes important in inflammation. Most striking in this context are several observations that TGR5 signalling curbs the inflammatory response of macrophages via interfering with NF-κB (nuclear factor κB) activity. In line with this, recent animal studies also suggest that TGR5 could be exploited as a potential target for intervention in a number of inflammation-driven diseases, including atherosclerosis. In the present paper, I review our current understanding of TGR5 with a strong focus on its potential as target for intervention in inflammation-driven diseases.


Subject(s)
Cardiovascular Diseases/metabolism , Inflammation/metabolism , Receptors, G-Protein-Coupled/metabolism , Atherosclerosis/metabolism , Bile Acids and Salts/metabolism , Glucagon-Like Peptide 1/metabolism , Humans
3.
ACS Med Chem Lett ; 4(12): 1158-62, 2013 Dec 12.
Article in English | MEDLINE | ID: mdl-24900622

ABSTRACT

TGR5 is a G-protein-coupled receptor (GPCR) mediating cellular responses to bile acids (BAs). Although some efforts have been devoted to generate homology models of TGR5 and draw structure-activity relationships of BAs, none of these studies has hitherto described how BAs bind to TGR5. Here, we present an integrated computational, chemical, and biological approach that has been instrumental to determine the binding mode of BAs to TGR5. As a result, key residues have been identified that are involved in mediating the binding of BAs to the receptor. Collectively, these results provide new hints to design potent and selective TGR5 agonists.

4.
Sci Rep ; 2: 430, 2012.
Article in English | MEDLINE | ID: mdl-22666533

ABSTRACT

Anionic exchange resins are bona fide cholesterol-lowering agents with glycemia lowering actions in diabetic patients. Potentiation of intestinal GLP-1 secretion has been proposed to contribute to the glycemia lowering effect of these non-systemic drugs. Here, we show that resin exposure enhances GLP-1 secretion and improves glycemic control in diet-induced animal models of "diabesity", effects which are critically dependent on TGR5, a G protein-coupled receptor that is activated by bile acids. We identified the colon as a major source of GLP-1 secretion after resin treatment. Furthermore, we demonstrate that the boost in GLP-1 release by resins is due to both enhanced TGR5-dependent production of the precursor transcript of GLP-1 as well as to the local enrichment of TGR5 agonists in the colon. Thus, TGR5 represents an essential component in the pathway mediating the enhanced GLP-1 release in response to anionic exchange resins.


Subject(s)
Anion Exchange Resins/pharmacology , Colon/drug effects , Glucagon-Like Peptide 1/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Bile Acids and Salts/pharmacology , Blood Glucose/metabolism , CHO Cells , Cholic Acids/pharmacology , Colon/metabolism , Cricetinae , Cricetulus , Diet, High-Fat/adverse effects , Enteroendocrine Cells/drug effects , Enteroendocrine Cells/metabolism , Glucagon-Like Peptide 1/blood , Glucagon-Like Peptide 1/genetics , Insulin/blood , Insulin Resistance/genetics , Male , Mice , Mice, Knockout , Obesity/blood , Obesity/etiology , Obesity/genetics , Proglucagon/genetics , Proglucagon/metabolism , Receptors, G-Protein-Coupled/genetics , Reverse Transcriptase Polymerase Chain Reaction
5.
Cell Metab ; 14(6): 747-57, 2011 Dec 07.
Article in English | MEDLINE | ID: mdl-22152303

ABSTRACT

The G protein-coupled receptor TGR5 has been identified as an important component of the bile acid signaling network, and its activation has been linked to enhanced energy expenditure and improved glycemic control. Here, we demonstrate that activation of TGR5 in macrophages by 6α-ethyl-23(S)-methylcholic acid (6-EMCA, INT-777), a semisynthetic BA, inhibits proinflammatory cytokine production, an effect mediated by TGR5-induced cAMP signaling and subsequent NF-κB inhibition. TGR5 activation attenuated atherosclerosis in Ldlr(-/-)Tgr5(+/+) mice but not in Ldlr(-/-)Tgr5(-/-) double-knockout mice. The inhibition of lesion formation was associated with decreased intraplaque inflammation and less plaque macrophage content. Furthermore, Ldlr(-/-) animals transplanted with Tgr5(-/-) bone marrow did not show an inhibition of atherosclerosis by INT-777, further establishing an important role of leukocytes in INT-777-mediated inhibition of vascular lesion formation. Taken together, these data attribute a significant immune modulating function to TGR5 activation in the prevention of atherosclerosis, an important facet of the metabolic syndrome.


Subject(s)
Atherosclerosis/prevention & control , Cholic Acids/pharmacology , Cytokines/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism , Signal Transduction/physiology , Analysis of Variance , Animals , Atherosclerosis/pathology , Blotting, Western , Bone Marrow Transplantation , Cyclic AMP/metabolism , DNA Primers/genetics , Flow Cytometry , Immunohistochemistry , Laser Capture Microdissection , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Knockout , Microscopy, Confocal , NF-kappa B/antagonists & inhibitors , Real-Time Polymerase Chain Reaction , Receptors, G-Protein-Coupled/genetics
6.
Dig Dis ; 29(1): 37-44, 2011.
Article in English | MEDLINE | ID: mdl-21691102

ABSTRACT

Bile acids (BAs) are amphipathic molecules that facilitate the uptake of lipids, and their levels fluctuate in the intestines as well as in the circulation depending on food intake. Besides their role in dietary lipid absorption, BAs function as signaling molecules that activate specific BA receptors and trigger downstream signaling cascades. The BA receptors and the signaling pathways they control are not only important in the regulation of BA synthesis and their metabolism, but they also regulate glucose homeostasis, lipid metabolism and energy expenditure - processes relevant in the context of the metabolic syndrome. In addition to the function of the nuclear receptor FXRα in regulating local effects of BAs in the organs of the enterohepatic axis, increasing evidence points to a crucial role of the G-protein-coupled receptor TGR5 in mediating systemic actions of BAs. Here we review the current knowledge on BA receptors, with a strong focus on the cell membrane receptor TGR5, which has emerged as a promising target for intervention in metabolic diseases.


Subject(s)
Bile Acids and Salts/metabolism , Cell Membrane/metabolism , Metabolic Diseases/therapy , Receptors, G-Protein-Coupled/metabolism , Animals , Humans , Signal Transduction
7.
J Hepatol ; 54(6): 1263-72, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21145931

ABSTRACT

Bile acids (BAs) are amphipathic molecules that facilitate the uptake of lipids, and their levels fluctuate in the intestine as well as in the blood circulation depending on food intake. Besides their role in dietary lipid absorption, bile acids function as signaling molecules capable to activate specific receptors. These BA receptors are not only important in the regulation of bile acid synthesis and their metabolism, but also regulate glucose homeostasis, lipid metabolism, and energy expenditure. These processes are important in diabetes and other facets of the metabolic syndrome, which represents a considerable increasing health burden. In addition to the function of the nuclear receptor FXRα in regulating local effects in the organs of the enterohepatic axis, increasing evidence points to a crucial role of the G-protein coupled receptor (GPCR) TGR5 in mediating systemic actions of BAs. Here we discuss the current knowledge on BA receptors, with a strong focus on the cell membrane receptor TGR5, which emerges as a valuable target for intervention in metabolic diseases.


Subject(s)
Bile Acids and Salts/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Glucose/metabolism , Humans , Immunologic Factors/metabolism , Inflammation/metabolism , Insulin Resistance , Liver/metabolism , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Mice , Models, Biological , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/genetics , Signal Transduction
8.
Circulation ; 121(18): 2023-32, 2010 May 11.
Article in English | MEDLINE | ID: mdl-20421523

ABSTRACT

BACKGROUND: Restenosis is the major drawback of percutaneous coronary interventions involving excessive activation and proliferation of vascular smooth muscle cells (SMCs). The nuclear receptor Nurr1 is an early response gene known mainly for its critical role in the development of dopamine neurons. In the present study, we investigated Nurr1 in human and experimental vascular restenosis. METHODS AND RESULTS: In a prospective cohort of 601 patients undergoing percutaneous coronary intervention, including stent placement, we found a strong association between Nurr1 haplotypes and in-stent restenosis risk. Furthermore, Nurr1 is specifically expressed in human in-stent restenosis and induced in cultured human SMCs in response to serum or tumor necrosis factor-alpha. Lentivirus-mediated gain- and loss-of-function experiments in SMCs demonstrated that overexpression of Nurr1 inhibited proliferation, consistent with increased expression of the key cell-cycle inhibitor p27(Kip1), whereas Nurr1 silencing enhanced SMC growth. The tumor necrosis factor-alpha-induced proinflammatory response of SMCs is inhibited by Nurr1, as reflected by reduced interleukin-1beta, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 expression. Consistent with our in vitro data, endogenous Nurr1 reduced wire injury-induced proliferation and vascular lesion formation in carotid arteries of ApoE(-/-) mice. CONCLUSIONS: Nurr1 haplotypes are associated with human restenosis risk, and Nurr1 is expressed in human in-stent restenosis. In SMCs, Nurr1 inhibits proliferation and inflammatory responses, which explains the inhibition of SMC-rich lesion formation in mice. The recently identified small-molecule drugs that enhance the activity of Nurr1 reveal this nuclear receptor as an attractive novel target for (local) intervention in restenosis.


Subject(s)
Coronary Artery Disease/genetics , Coronary Restenosis/genetics , Muscle, Smooth, Vascular/pathology , Nuclear Receptor Subfamily 4, Group A, Member 2/genetics , Vasculitis/genetics , Angioplasty, Balloon, Coronary , Animals , Apolipoproteins E/genetics , Cell Division/physiology , Cells, Cultured , Coronary Artery Disease/epidemiology , Coronary Artery Disease/therapy , Coronary Restenosis/epidemiology , Coronary Restenosis/pathology , Coronary Vessels/immunology , Coronary Vessels/pathology , Coronary Vessels/physiopathology , Disease Models, Animal , Female , Genetic Predisposition to Disease/epidemiology , Haplotypes , Humans , Linkage Disequilibrium , Mice , Mice, Mutant Strains , Muscle, Smooth, Vascular/physiology , Neovascularization, Physiologic/physiology , Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism , Risk Factors , Stents , Vasculitis/epidemiology , Vasculitis/pathology
9.
Arterioscler Thromb Vasc Biol ; 30(8): 1591-7, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20413732

ABSTRACT

OBJECTIVE: 6-Mercaptopurine (6-MP), the active metabolite of the immunosuppressive prodrug azathioprine, is commonly used in autoimmune diseases and transplant recipients, who are at high risk for cardiovascular disease. Here, we aimed to gain knowledge on the action of 6-MP in atherosclerosis, with a focus on monocytes and macrophages. METHODS AND RESULTS: We demonstrate that 6-MP induces apoptosis of THP-1 monocytes, involving decreased expression of the intrinsic antiapoptotic factors B-cell CLL/Lymphoma-2 (Bcl-2) and Bcl2-like 1 (Bcl-x(L)). In addition, we show that 6-MP decreases expression of the monocyte adhesion molecules platelet endothelial adhesion molecule-1 (PECAM-1) and very late antigen-4 (VLA-4) and inhibits monocyte adhesion. Screening of a panel of cytokines relevant to atherosclerosis revealed that 6-MP robustly inhibits monocyte chemoattractant chemokine-1 (MCP-1) expression in macrophages stimulated with lipopolysaccharide (LPS). Finally, local delivery of 6-MP to the vessel wall, using a drug-eluting cuff, attenuates atherosclerosis in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice (P<0.05). In line with our in vitro data, this inhibition of atherosclerosis by 6-MP was accompanied with decreased lesion monocyte chemoattractant chemokine-1 levels, enhanced vascular apoptosis, and reduced macrophage content. CONCLUSIONS: We report novel, previously unrecognized atheroprotective actions of 6-MP in cultured monocytes/macrophages and in a mouse model of atherosclerosis, providing further insight into the effect of the immunosuppressive drug azathioprine in atherosclerosis.


Subject(s)
Apolipoprotein E3/metabolism , Atherosclerosis/prevention & control , Immunosuppressive Agents/pharmacology , Macrophages/drug effects , Mercaptopurine/pharmacology , Monocytes/drug effects , Animals , Apolipoprotein E3/genetics , Apoptosis/drug effects , Atherosclerosis/genetics , Atherosclerosis/immunology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cell Adhesion/drug effects , Cells, Cultured , Chemokine CCL2/metabolism , Chemotaxis/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Immunosuppressive Agents/administration & dosage , Inflammation Mediators/metabolism , Integrin alpha4beta1/metabolism , Macrophages/immunology , Macrophages/metabolism , Macrophages/pathology , Male , Mercaptopurine/administration & dosage , Mice , Mice, Inbred C57BL , Mice, Transgenic , Monocytes/immunology , Monocytes/metabolism , Monocytes/pathology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Time Factors , bcl-X Protein/metabolism
11.
Biochem Biophys Res Commun ; 366(4): 910-6, 2008 Feb 22.
Article in English | MEDLINE | ID: mdl-18086558

ABSTRACT

NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor, and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity.


Subject(s)
DNA-Binding Proteins/metabolism , Lipid Metabolism , Liver/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Sterol Regulatory Element Binding Protein 1/antagonists & inhibitors , Transcription Factors/metabolism , Adenoviridae , Animals , Gene Expression Regulation , Liver/cytology , Male , Mice , Mice, Inbred C57BL , Nuclear Receptor Subfamily 4, Group A, Member 1 , RNA, Messenger/genetics , RNA, Messenger/metabolism , Triglycerides/blood
12.
Curr Opin Lipidol ; 18(5): 515-20, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17885421

ABSTRACT

PURPOSE OF REVIEW: The nuclear orphan receptors Nur77 (NR4A1), Nurr1 (NR4A2) and NOR-1 (NR4A3) are known to be involved in T-cell apoptosis, brain development, and the hypothalamic-pituitary-adrenal axis. Here, we review our current understanding of the NR4A nuclear receptors in processes that are relevant to vascular disease. RECENT FINDINGS: NR4A nuclear receptors have recently been described to play a role in metabolism by regulating gluconeogenesis, lipolysis, energy expenditure, and adipogenesis. The function of NR4A nuclear receptors has also extensively been investigated in cells crucial in vascular lesion formation, such as macrophages, endothelial cells and smooth muscle cells. SUMMARY: The involvement of NR4A nuclear receptors in both metabolism and in processes in the vessel wall supports a substantial role for NR4A nuclear receptors in the development of vascular disease.


Subject(s)
Receptors, Cytoplasmic and Nuclear/metabolism , Transcription Factors/metabolism , Vascular Diseases/metabolism , Animals , Atherosclerosis/metabolism , Atherosclerosis/pathology , Atherosclerosis/physiopathology , Coronary Restenosis/metabolism , Coronary Restenosis/pathology , Coronary Restenosis/physiopathology , Humans , Inflammation/metabolism , Inflammation/pathology , Inflammation/physiopathology , Models, Biological , Receptors, Cytoplasmic and Nuclear/physiology , Transcription Factors/physiology , Vascular Diseases/pathology , Vascular Diseases/physiopathology
13.
Trends Cardiovasc Med ; 17(3): 105-11, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17418373

ABSTRACT

Nur77, Nurr1, and NOR-1 form the NR4A subfamily of the nuclear hormone receptor superfamily of transcription factors and have been described in the regulation of differentiation, proliferation, apoptosis, and survival of many different cell types. The expression of NR4A nuclear receptors in vascular pathologies has only recently been revealed, after which studies on the functional involvement of NR4A receptors in vascular disease were initiated. This review summarizes our current view on involvement of Nur77, Nurr1, and NOR-1 in atherosclerotic vascular disease and discusses NR4A function in vascular response to injury.


Subject(s)
Atherosclerosis/metabolism , DNA-Binding Proteins/metabolism , Graft Occlusion, Vascular/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Transcription Factors/metabolism , Animals , Apoptosis , Atherosclerosis/pathology , Cell Differentiation , Cell Proliferation , Cell Survival , Graft Occlusion, Vascular/pathology , Humans , Membrane Transport Proteins/metabolism , Muscle, Smooth, Vascular/blood supply , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/metabolism , Nerve Tissue Proteins/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1 , Nuclear Receptor Subfamily 4, Group A, Member 2 , Receptors, Cell Surface/metabolism
14.
Circulation ; 115(4): 493-500, 2007 Jan 30.
Article in English | MEDLINE | ID: mdl-17242285

ABSTRACT

BACKGROUND: Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated that 6-mercaptopurine (6-MP) enhances Nur77 activity. We hypothesized that 6-MP inhibits neointima formation through activation of Nur77. METHODS AND RESULTS: It is demonstrated that 6-MP increases Nur77 activity in cultured SMCs, which results in reduced [3H]thymidine incorporation, whereas Nur77 small interfering RNA knockdown partially restores DNA synthesis. Furthermore, we studied the effect of 6-MP in a murine model of cuff-induced neointima formation. Nur77 mRNA is upregulated in cuffed arteries, with optimal expression after 6 hours and elevated expression up to 7 days after vascular injury. Local perivascular delivery of 6-MP with a drug-eluting cuff significantly inhibits neointima formation in wild-type mice. Locally applied 6-MP does not affect inflammatory responses or apoptosis but inhibits expression of proliferating cell nuclear antigen and enhances protein levels of the cell-cycle inhibitor p27(Kip1) in the vessel wall. An even stronger inhibition of neointima formation in response to local 6-MP delivery was observed in transgenic mice that overexpressed Nur77. In contrast, 6-MP does not alter lesion formation in transgenic mice that overexpress a dominant-negative variant of Nur77 in arterial SMCs, which provides evidence for the involvement of Nur77-like factors. CONCLUSIONS: Enhancement of the activity of Nur77 by 6-MP protects against excessive SMC proliferation and SMC-rich neointima formation. We propose that activation of the nuclear receptor Nur77 is a rational approach to treating in-stent restenosis.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Coronary Restenosis/drug therapy , DNA-Binding Proteins/metabolism , Mercaptopurine/pharmacology , Muscle, Smooth, Vascular/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Transcription Factors/metabolism , Animals , Apoptosis/drug effects , Cell Division/drug effects , Cells, Cultured , Coronary Restenosis/metabolism , Coronary Restenosis/pathology , DNA-Binding Proteins/genetics , Disease Models, Animal , Drug Implants , Femoral Artery/pathology , Humans , Male , Mice , Mice, Inbred Strains , Mice, Transgenic , Muscle, Smooth, Vascular/pathology , Nuclear Receptor Subfamily 4, Group A, Member 1 , RNA, Messenger/metabolism , RNA, Small Interfering , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Steroid/genetics , Transcription Factors/genetics , Tunica Intima/drug effects , Tunica Intima/pathology , Umbilical Arteries/cytology
15.
Arterioscler Thromb Vasc Biol ; 26(10): 2288-94, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16873729

ABSTRACT

OBJECTIVE: Atherosclerosis is an inflammatory disease in which macrophage activation and lipid loading play a crucial role. In this study, we investigated expression and function of the NR4A nuclear receptor family, comprising Nur77 (NR4A1, TR3), Nurr1 (NR4A2), and NOR-1 (NR4A3) in human macrophages. METHODS AND RESULTS: Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry. Protein expression localizes to the nucleus. Primary and THP-1 macrophages transiently express NR4A-factors in response to lipopolysaccharide and tumor necrosis factor alpha. Lentiviral overexpression of Nur77, Nurr1, or NOR-1 reduces expression and production of interleukin (IL)-1beta and IL-6 proinflammatory cytokines and IL-8, macrophage inflammatory protein-1alpha and -1beta and monocyte chemoattractant protein-1 chemokines. In addition, NR4A-factors reduce oxidized-low-density lipoprotein uptake, consistent with downregulation of scavenger receptor-A, CD36, and CD11b macrophage marker genes. Knockdown of Nur77 or NOR-1 with gene-specific lentiviral short-hairpin RNAs resulted in enhanced cytokine and chemokine synthesis, increased lipid loading, and augmented CD11b expression, demonstrating endogenous NR4A-factors to inhibit macrophage activation, foam-cell formation, and differentiation. CONCLUSIONS: NR4A-factors are expressed in human atherosclerotic lesion macrophages and reduce human macrophage lipid loading and inflammatory responses, providing further evidence for a protective role of NR4A-factors in atherogenesis.


Subject(s)
Atherosclerosis/metabolism , DNA-Binding Proteins/metabolism , Inflammation/prevention & control , Lipid Metabolism , Macrophages/metabolism , Membrane Transport Proteins/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Transcription Factors/metabolism , Atherosclerosis/pathology , Chemokines/antagonists & inhibitors , Cytokines/antagonists & inhibitors , DNA-Binding Proteins/genetics , Gene Transfer Techniques , Genetic Vectors , Humans , Inflammation Mediators/antagonists & inhibitors , Lentivirus/genetics , Lipopolysaccharides/pharmacology , Lipoproteins, LDL/antagonists & inhibitors , Macrophages/drug effects , Membrane Transport Proteins/genetics , Nuclear Receptor Subfamily 4, Group A, Member 1 , Nuclear Receptor Subfamily 4, Group A, Member 2 , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Steroid/genetics , Transcription Factors/genetics
16.
J Immunol ; 176(9): 5213-22, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16621986

ABSTRACT

The promising, but modest, clinical results of many human cancer vaccines indicate a need for vaccine adjuvants that can increase both the quantity and the quality of vaccine-induced, tumor-specific T cells. In this study we tested the immunological and antitumor effects of the proinflammatory cytokine, IL-23, in gp100 peptide vaccine therapy of established murine melanoma. Neither systemic nor local IL-23 alone had any impact on tumor growth or tumor-specific T cell numbers. Upon specific vaccination, however, systemic IL-23 greatly increased the relative and absolute numbers of vaccine-induced CD8(+) T cells and enhanced their effector function at the tumor site. Although IL-23 specifically increased IFN-gamma production by tumor-specific T cells, IFN-gamma itself was not a primary mediator of the vaccine adjuvant effect. The IL-23-induced antitumor effect and accompanying reversible weight loss were both partially mediated by TNF-alpha. In contrast, local expression of IL-23 at the tumor site maintained antitumor activity in the absence of weight loss. Under these conditions, it was also clear that enhanced effector function of vaccine-induced CD8(+) T cells, rather than increased T cell number, is a primary mechanism underlying the antitumor effect of IL-23. Collectively, these results suggest that IL-23 is a potent vaccine adjuvant for the induction of therapeutic, tumor-specific CD8(+) T cell responses.


Subject(s)
Adjuvants, Immunologic , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacology , Cancer Vaccines/immunology , Cancer Vaccines/pharmacology , Interleukins/immunology , Animals , Antigens/immunology , Antineoplastic Agents/administration & dosage , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cancer Vaccines/pharmacokinetics , Cell Proliferation/drug effects , Cells, Cultured , Interferon-gamma/biosynthesis , Interleukin-23 , Interleukin-23 Subunit p19 , Interleukins/administration & dosage , Mice , Time Factors , Tumor Necrosis Factor-alpha/metabolism , Weight Loss/drug effects , Xenograft Model Antitumor Assays
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