The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation

Ricote, Mercedes; Li, Andrew C.; Willson, Timothy M.; Kelly, Carolyn; Glass, Christopher K.

doi:10.1038/34178

Cited by 3,355 publications

(2,834 citation statements)

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“…38 Carbon monoxide, a main product of heme oxygenase-1-mediated heme degradation, induces the expression of the transcription factor PPARg in macrophages 39 that drives antiinflammatory activation in macrophages and promotes adipogenesis and adipocyte function. 40,41 Thus, heme oxygenase-1 has a putative beneficial function in adipose tissue through antioxidative, metabolic and anti-inflammatory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

et al. 2009

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Objective: Insulin resistance in visceral obesity is substantially driven by adipose tissue inflammation, particularly by macrophages accumulating in obese adipose tissue. In contrast, adipose tissue macrophages express the hemoglobin scavenger receptor (CD163) and heme oxygenase-1 (gene: HMOX1) that together protect from oxidative stress. Our aim was to evaluate the expression of CD163 and HMOX1 in intra-abdominal visceral (omental) and subcutaneous adipose tissue as well as circulating soluble CD163 concentrations in human obesity and its association with adipose tissue inflammation, body fat distribution and insulin resistance. Methods: CD163, HMOX1 and CD68 mRNA expression in visceral and subcutaneous adipose tissue, serum concentration of soluble CD163 in morbidly obese patients (body mass index (BMI) 440 kg m À2 ), who underwent laparoscopic surgery for gastric banding (n ¼ 20), matched for age and sex to controls (BMIo30 kg m À2 ; n ¼ 20) was analyzed. Results: CD163 expression was highly upregulated in human adipose tissue and soluble CD163 serum concentration was elevated in obese vs lean subjects. HMOX1 was upregulated in adipose tissue by obesity as well and expressed predominantly in macrophages. Although CD163 expression strictly correlated with macrophage abundance, HMOX1 was additionally upregulated within macrophages. This upregulation was significantly lower in visceral compared with subcutaneous adipose tissue. Strikingly, relative visceral adipose tissue expression of HMOX1 negatively correlated with waist-to-hip ratio and the homeostasis model assessment of insulin resistance (both P ¼ 0.024). Conclusions: Visceral obesity is associated with defective upregulation of heme oxygenase-1 in visceral adipose tissue. A lack of this antioxidative and anti-inflammatory enzyme in visceral adipose tissue could contribute to the development of insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

et al. 2009

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“…PPAR␥ has recently been suggested to function as a negative regulator of inflammatory responses. PPAR␥ ligands are capable of reducing the expression of genes for cytokines (e.g., TNF␣, IL-6, and IL-1␤), iNOS, gelatinase B, scavenger receptor A, and COX-2 in activated macrophages (9,10,26).…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence has indicated that PPAR␥ has diverse effects on a wide variety of cells and plays a crucial role in the regulation of monocyte differentiation, atherosclerosis, immune responses, apoptosis, and carcinogenesis (8). Of particular interest is the possibility that it may exert an antiinflammatory effect by inhibiting the gene expression of proinflammatory cytokines, inducible nitric oxide synthase (iNOS), proteinases, and cyclooxygenase (COX) (9,10). In order to elucidate the regulatory mechanisms that cause acute gout to resolve, we conducted experiments investigating the expression of PPAR␥ by MSU crystal-stimulated monocytes and the therapeutic effect of PPAR␥ ligands on crystal-induced acute inflammation.…”

mentioning

confidence: 99%

Rapid induction of peroxisome proliferator–activated receptor γ expression in human monocytes by monosodium urate monohydrate crystals

Akahoshi¹,

Namai²,

Murakami³

et al. 2003

Arthritis & Rheumatism

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Objective. Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR␥ in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR␥ expression by monosodium urate monohydrate (MSU) crystal-stimulated monocytes, and we studied the effects of PPAR␥ ligands on crystal-induced acute inflammation.Methods. PPAR␥ expression by MSU crystalstimulated human peripheral blood mononuclear cells was determined by reverse transcription-polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR␥ ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated.Results. MSU crystals rapidly and selectively induced PPAR␥ expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR␥ was functional, since a PPAR␥ ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR␥, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15deoxy-PGJ 2 ), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ 2 significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal-induced acute inflammation.Conclusion. Rapid induction of PPAR␥ expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout.

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“…To establish that IL-13 regulates CD36 expression through PPARc, we performed transfection experiments on the murine Mu cell line RAW264.7, which expresses very low levels of PPARc mRNA [25]. IL-13 and rosiglitazone did not induce an increase in CD36 expression in this cell line transiently transfected with a control plasmid (RSV-bGal) (Fig.…”

Section: Il-13 Regulates Cd36 Expression Through Pparcmentioning

confidence: 99%

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

et al. 2007

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The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)c pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARc pathway was demonstrated using transfection of a PPARc expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARc, and in peritoneal macrophages from PPARc-conditional null mice. We also show that CD36 induction by IL-13 via PPARc is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-D 12,14 -prostaglandin J 2 , an endogenous PPARc ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARc are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARc in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARc ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.Leukocyte signaling * These 2 authors contributed equally to this work. IntroductionThe innate immune system protects the host in the early phase of infection. Circulating monocytes and tissue macrophages (Mu) mediate much of this innate immune response [1]. The strategy of recognition in the innate response is mediated by the coordinated action of pathogen-associated molecular patterns and pattern recognition receptors. Scavenger receptors and mannose receptor are important pattern recognition receptors in monocytes/Mu [2,3]. The modulation of the expression of these receptors may be critical in the role of these cells in antigen processing, scavenging, and host defence against pathogens. Several members of the scavenger receptor family, including Mu class A scavenger receptors and CD36, have been identified as receptors for modified lipoproteins on Mu, and their relevance to lipid uptake has been demonstrated in vitro and in vivo [4]. The scavenger receptor CD36, an 88-kDa integral membrane protein, is a class B scavenger receptor expressed on a wide variety of cells, in particular on monocytes and monocytederived Mu [5,6]. CD36 is known as a receptor for the uptake of oxidatively modified low-density lipoprotein (LDL) [7] and is also able to bind anionic phospholipid phosphatidylserine [8]. This scavenger receptor is implicated in the clearance of apoptotic cells [9]. Recently, McGilvray and colleagues [10] described a CD36-dependent nonopsonic phagocytosis of erythrocytes containing P. falciparum, by monocytes and culture-derived Mu, and a decrease in the parasiteinduced TNF secretion by monocytes/Mu. These processes were accentuated by CD36 up-regulation by peroxisome proliferator-acti...

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The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation

Cited by 3,355 publications

References 23 publications

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

Rapid induction of peroxisome proliferator–activated receptor γ expression in human monocytes by monosodium urate monohydrate crystals

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

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