Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARγ

Ge, Heng; Zhang, Junfeng; Guo, Bing-shi; He, Qing; Wang, Binyao; He, Ben; Wang, Changqian

doi:10.1016/j.vph.2006.08.412

Cited by 56 publications

(32 citation statements)

References 35 publications

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“…Support for this hypothesis comes from studies showing that RSV activates PPARg in CaCo2 cells (38) and macrophages (39). Additionally, our data show that RSV robustly induces PPARg activity and prevents CLAmediated suppression of TZD-induced PPARg activation (Fig.…”

Section: Discussionsupporting

confidence: 73%

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol

Kennedy

Overman

LaPoint

et al. 2009

Journal of Lipid Research

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Inflammation plays a role in trans-10, cis-12 (10,12)-conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal-related kinase and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1b) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin pathway involving phospholipase A 2 , cyclooxygenase-2, and PGF 2a . In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species associated with cellular stress, and activation of stress-related proteins (i.e., activating transcription factor 3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Finally, 10,12 CLA-mediated decrease of peroxisome proliferator-activated receptor g (PPARg) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of PPRE, suggesting that RSV increases PPARg activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLAmediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPARg activity. Feeding a mixture of conjugated linoleic acid (CLA) isomers [i.e., trans-10, cis-12 (10,12) CLA and cis-9, trans-11 (9,11) CLA] reduces adiposity in animals (1) and some humans (2). The triglyceride (TG)-lowering properties of CLA appear to be due exclusively to the 10,12 isomer (3-5), and involve decreased uptake and metabolism of glucose and fatty acids (FA)s (6), and increased lipolysis (7) in adipocytes. These anti-obesity properties of 10,12 CLA are dependent on the activation of mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) (6) and nuclear factor kB (NFkB) (8, 9) in adipocytes. These signaling pathways induced by 10,12 CLA are linked to the induction and secretion of cytokines (8, 9), which are known to antagonize peroxisome proliferator-activated receptor g (PPARg) target gene expression and insulin sensitivity (10-15). Consistent with these data, 10,12 CLA supplementation of humans is associated with hyperglycemia, insulin resistance, elevated levels of inflammatory prostaglandins (PGs) and cytokines, and dyslipidemia (16)(17)(18).Recently, supplementation of mice and 3T3-L1 adipocytes with 10,12 CLA has been shown to activate the integrated stress response (ISR) pathway (19), which is linked to inflammation, insulin resistance, and endoplasmic reticulum (ER) stress (20). Cellular stress can be caused by a relatively disproportional influx of macronutrients that adversely affect organelle function, including the mitoc...

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Section: Discussionsupporting

confidence: 73%

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol

Kennedy

Overman

LaPoint

et al. 2009

Journal of Lipid Research

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“…Genes inhibited by both t-RESV and PPARg ligands include proinflammatory cytokines, such as TNF-a, and CAMs, such as VCAM-1 or ICAM-1. Some reports have demonstrated that t-RESV activates PPARg in cell types other than those studied in this work (52,53). In the current study, t-RESV increased PPARg expression in human mononuclear and endothelial cells.…”

Section: Discussionsupporting

confidence: 66%

Trans- but Not Cis-Resveratrol Impairs Angiotensin-II–Mediated Vascular Inflammation through Inhibition of NF-κB Activation and Peroxisome Proliferator-Activated Receptor-γ Upregulation

Rius¹,

Abu-Taha²,

Hermenegildo

et al. 2010

The Journal of Immunology

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Angiotensin II (Ang-II) displays inflammatory activity and is implicated in several cardiovascular disorders. This study evaluates the effect of cis- and trans (t)-resveratrol (RESV) in two in vivo models of vascular inflammation and identifies the cardioprotective mechanisms that underlie them. In vivo, Ang-II–induced arteriolar leukocyte adhesion was inhibited by 71% by t-RESV (2.1 mg/kg, i.v.), but was not affected by cis-RESV. Because estrogens influence the rennin-angiotensin system, chronic treatment with t-RESV (15 mg/kg/day, orally) inhibited ovariectomy-induced arteriolar leukocyte adhesion by 81%, partly through a reduction of cell adhesion molecule (CAM) expression and circulating levels of cytokine-induced neutrophil chemoattractant, MCP-1, and MIP-1α. In an in vitro flow chamber system, t-RESV (1–10 μM) undermined the adhesion of human leukocytes under physiological flow to Ang-II–activated human endothelial cells. These effects were accompanied by reductions in monocyte and endothelial CAM expression, chemokine release, phosphorylation of p38 MAPK, and phosphorylation of the p65 subunit of NF-κB. Interestingly, t-RESV increased the expression of peroxisome proliferator-activated receptor-γ in human endothelial and mononuclear cells. These results demonstrate for the first time that the in vivo anti-inflammatory activity of RESV is produced by its t-RESV, which possibly interferes with signaling pathways that cause the upregulation of CAMs and chemokine release. Upregulation of proliferator-activated receptor-γ also appears to be involved in the cardioprotective effects of t-RESV. In this way, chronic administration of t-RESV may reduce the systemic inflammatory response associated with the activation of the rennin-angiotensin system, thereby decreasing the risk of further cardiovascular disease.

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“…With regard to the regulation of CD147 expression, several signaling pathways are reported to be associated with its transcription (18)(19)(20)(21)(22)(23). The core promoter and transcription factor-binding sites of CD147 were previously analyzed and identified as targets of the cancer-associated transcription factors c-Myc and Sp1 (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…With regard to the regulation of the expression of CD147, several signaling pathways are reported to be associated with its gene transcription (18)(19)(20)(21)(22)(23). In particular, the expression of CD147 is reported to be positively regulated by p38-, Erk1/2-and JNK-dependent MAPK signaling pathways and the c-Myc protein (18,19,21,22).…”

Section: Ad-reic Downregulates the Expression Of Cd147 Without Dependmentioning

confidence: 99%

Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells

et al. 2017

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Abstract. Our group previously developed an adenoviral vector encoding the REIC/Dkk-3 gene (Ad-REIC), a tumor suppressor, for cancer gene therapy. The Ad-REIC agent induces apoptosis and inhibits invasion in a number of cancer cell lines; however, the molecular mechanisms underlying its effects remain unclear. Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a key molecule that promotes cancer proliferation and invasion. In order to elucidate the therapeutic mechanism of Ad-REIC, its effect on the expression of CD147 in human bladder cancer KK47 cells was investigated. Treatment with Ad-REIC markedly downregulated the expression of CD147 and significantly inhibited cellular proliferation. Since the expression of CD147 is reported to be under the positive control of mitogen-activated protein kinase (MAPK) signaling and the c-Myc protein, the correlations between the expression of CD147 and the activation of MAPKs or the expression of c-Myc were examined. Unexpectedly, no positive correlation was observed between the level of CD147 and the potential regulators that were assessed, indicating that another signaling pathway is responsible for the downregulation of CD147. The results from the present study demonstrate that Ad-REIC treatment can significantly downregulate the expression of CD147 in bladder cancer cells. Downregulation of the cancer-progression factor CD147 may be a novel mechanism that underlies the therapeutic effects of Ad-REIC treatment.

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Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARγ

Cited by 56 publications

References 35 publications

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol

Trans- but Not Cis-Resveratrol Impairs Angiotensin-II–Mediated Vascular Inflammation through Inhibition of NF-κB Activation and Peroxisome Proliferator-Activated Receptor-γ Upregulation

Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells

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