Role for Peroxisome Proliferator-Activated Receptor α in Oxidized Phospholipid–Induced Synthesis of Monocyte Chemotactic Protein-1 and Interleukin-8 by Endothelial Cells

Lee, Hans C.; Shi, Weibin; Tontonoz, Peter; Wang, Shirley; Subbanagounder, Ganesamoorthy; Hedrick, Catherine C.; Hama, Susan; Borromeo, Christine; Evans, Ronald M.; Berliner, Judith A.; Nagy, László

doi:10.1161/01.res.87.6.516

Cited by 272 publications

(234 citation statements)

References 40 publications

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“…Although these compounds have same antimitotic and antitumor activities as 15d-PGJ 2 , whether they can function through a PPAR␥-dependent pathway still remains unknown (35). A recent study demonstrated that activation of PPAR␣ with the synthetic ligand WY-14643 stimulates the synthesis of IL-8 and MCP-1 by human aortic endothelial cells (22). In our current study of monocytes/macrophages models, we did not observe any significant induction effect of WY-14643 on IL-8 gene expression.…”

Section: Discussioncontrasting

confidence: 69%

Differential Regulation of Chemokine Gene Expression by 15-Deoxy-Δ12,1412,14 Prostaglandin J2

Zhang

Wang

Mukaida

et al. 2001

The Journal of Immunology

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Ligands for peroxisome proliferator-activated receptor γ (PPARγ), such as 15-deoxy-Δ12,14PGJ2 (15d-PGJ2) have been proposed as a new class of antiinflammatory compounds with possible clinical applications. As there is some controversy over the inhibitory effects of 15d-PGJ2 on chemokine gene expression, we investigated whether 15d-PGJ2 itself affected chemokine gene expression in human monocytes/macrophages and two monocytic cell lines. Here we demonstrate that the 15d-PGJ2 can induce IL-8 gene expression. In contrast, monocyte chemoattractant protein-1 gene expression was suppressed by 15d-PGJ2, while the expression of RANTES was unaltered. Furthermore, concomitant treatment of monocytes/macrophages with 15d-PGJ2 (2.5 × 10−6 M) potentiated LPS-induced gene expression of IL-8 mRNA, but suppressed PMA-induction of IL-8 mRNA. In addition, treatment of U937 and THP-1 cells with 15d-PGJ2 also resulted in induction of IL-8 gene expression. Further studies demonstrated that 15d-PGJ2 regulated IL-8 gene expression via a ligand-specific and PPARγ-dependent pathway. Our observations revealed a previous unappreciated function and mechanism of 15d-PGJ2-mediated regulation of cytokine gene expression in monocytes/macrophages.

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Section: Discussioncontrasting

confidence: 69%

Differential Regulation of Chemokine Gene Expression by 15-Deoxy-Δ12,1412,14 Prostaglandin J2

Zhang

Wang

Mukaida

et al. 2001

The Journal of Immunology

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“…PPAR␥, in contrast to PPAR␣, is aberrantly expressed in atherosclerotic lesions (20) and colonic tumors (44), which provide phospholipid oxidation products with the potential to alter the complement of genes expressed in such areas. Certain synthetic diacyl phospholipid oxidation products modestly activate PPAR␣ function (12). However, PPAR␣ activation by oxidized phospholipids depends on phospholipase A 2 activity (13), suggesting that the oxidized free fatty acid products of this reaction are the actual ligands for PPAR␣.…”

Section: ϫ261mentioning

confidence: 99%

“…This process also creates PPAR␣ ligands (12,13), the bulk of which depend on liberation by phospholipase A 2 to free fatty acid oxidation products (13). PPAR␣ alters lipid metabolism, enhances lipid oxidation, and often dampens inflammatory events and signaling pathways (14,15).…”

mentioning

confidence: 99%

Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-activated Receptor γ Ligands and Agonists

Davies¹,

Pontsler²,

Marathe³

et al. 2001

Journal of Biological Chemistry

253

197

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Synthetic high affinity peroxisome proliferator-activated receptor (PPAR) agonists are known, but biologic ligands are of low affinity. Oxidized low density lipoprotein (oxLDL) is inflammatory and signals through PPARs. We showed, by phospholipase A 1 digestion, that PPAR␥ agonists in oxLDL arise from the small pool of alkyl phosphatidylcholines in LDL. We identified an abundant oxidatively fragmented alkyl phospholipid in oxLDL, hexadecyl azelaoyl phosphatidylcholine (azPC), as a high affinity ligand and agonist for PPAR␥. [ 3 H]azPC bound recombinant PPAR␥ with an affinity (K d(app) Ϸ40 nM) that was equivalent to rosiglitazone (BRL49653), and competition with rosiglitazone showed that binding occurred in the ligand-binding pocket. azPC induced PPRE reporter gene expression, as did rosiglitazone, with a half-maximal effect at 100 nM. Overexpression of PPAR␣ or PPAR␥ revealed that azPC was a specific PPAR␥ agonist. The scavenger receptor CD36 is encoded by a PPRE-responsive gene, and azPC enhanced expression of CD36 in primary human monocytes. We found that anti-CD36 inhibited azPC uptake, and it inhibited PPRE reporter induction. Results with a small molecule phospholipid flippase mimetic suggest azPC acts intracellularly and that cellular azPC accumulation was efficient. Thus, certain alkyl phospholipid oxidation products in oxLDL are specific, high affinity extracellular ligands and agonists for PPAR␥ that induce PPAR-responsive genes.The transcription factor PPAR␥, 1 in association with its 9-cis-retinoate-binding RXR partner, controls metabolic and cellular differentiation genes that contain variations of a cognate PPAR-response element (1). PPAR␥, like other members of the broad nuclear hormone receptor family, undergoes a conformational change when it binds specific lipid ligands. This structural reorganization alters its associated proteins, releasing transcriptional inhibitors and recruiting transcriptional co-activators. The regulation of PPAR␥ function is therefore controlled by lipid ligand binding.A number of synthetic ligands for PPAR␥ are known. One of these, rosiglitazone (BRL49653), binds with high affinity and is widely prescribed as an insulin sensitizer in type II diabetes. However, defining relevant biologic ligands has been problematic. Several oxidatively modified fatty acids bind and activate PPAR␥, including 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ), other arachidonate metabolites (2, 3), the linoleate derivatives 9-HODE and 13-HODE (4), and several free fatty acids (5, 6). However, none of these are particularly potent agonists, and for some their presence at concentrations sufficient to activate PPAR␥ can be questioned. For example, the oxygenated fatty acid products described above do not confer much advantage in potency over activation by free arachidonate (7) where a concentration of several micromolar is required to elicit a response. Moreover, the 9-and 13-HODEs and their peroxides found in oxidized LDL (8) or in skin exposed to the tumor promoter phorbol myristate ace...

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“…The effects of free fatty acids are likely to be mediated by PPAR␣, which is abundantly expressed in endothelial cells and drives the expression of IL-8 in these cells. 30 However, in contrast to endothelial cells, macrophages strongly express PPAR␥ rather than PPAR␣, 30,31 and the ligands of PPAR␥ have been shown to induce expression of IL-8 in human macrophages. 32 Yet involvement of PPAR␥ in the H-LDL-induced cytokine secretion appears unlikely, because H-LDL effectively activated both NF-B and AP-1 whereas PPAR␥ downregulates NF-B and AP-1 activation and the transcription of proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Low-Density Lipoprotein Modified by Macrophage-Derived Lysosomal Hydrolases Induces Expression and Secretion of IL-8 Via p38 MAPK and NF-κB by Human Monocyte-Derived Macrophages

Hakala

Lindstedt

Kovanen

et al. 2006

ATVB

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Objective-Modified lipoproteins induce inflammatory reactions in the atherosclerotic arterial wall. We have previously found that macrophages in atherosclerotic lesions secrete lysosomal hydrolases that can modify low-density-lipoprotein (LDL) in vitro to generate "hydrolase-modified LDL" (H-LDL). Here, we studied whether H-LDL exerts inflammatory effects on cultured human macrophages. Methods and Results-Using cytokine cDNA arrays, we found that H-LDL induced expression of IL-8, but not of the anti-inflammatory cytokines IL-10 and transforming growth factor (TGF)-␤, in human monocyte-derived macrophages. H-LDL induced rapid phosphorylation of the p38 mitogen-activated protein kinase (MAPK), nuclear translocation of 2 transcription factors, nuclear factor B (NF-B) and activator protein 1 (AP-1), and time-dependent secretion of IL-8 from the macrophages. Inhibition of MAPKs and of transcription factors showed that p38 MAPK and NF-B, but not ERK1/2, JNK, or AP-1, were crucial for the H-LDL-induced IL-8 secretion from the macrophages. Conclusions-The results show that by activating p38 MAPK and NF-B, macrophage hydrolases modify LDL into biologically active particles capable of triggering the secretion of IL-8 in macrophages. Thus, activated hydrolasesecreting macrophages in atherosclerotic lesions may sustain a proatherogenic extracellular environment by hydrolyzing LDL and triggering it to act in an autocrine or paracrine fashion to induce IL-8 secretion by the plaque macrophages.

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Role for Peroxisome Proliferator-Activated Receptor α in Oxidized Phospholipid–Induced Synthesis of Monocyte Chemotactic Protein-1 and Interleukin-8 by Endothelial Cells

Cited by 272 publications

References 40 publications

Differential Regulation of Chemokine Gene Expression by 15-Deoxy-Δ12,1412,14 Prostaglandin J2

Differential Regulation of Chemokine Gene Expression by 15-Deoxy-Δ12,1412,14 Prostaglandin J2

Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-activated Receptor γ Ligands and Agonists

Low-Density Lipoprotein Modified by Macrophage-Derived Lysosomal Hydrolases Induces Expression and Secretion of IL-8 Via p38 MAPK and NF-κB by Human Monocyte-Derived Macrophages

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