Targeting Nuclear Hormone Receptors: PPAR<i>α</i>Agonists as Potential Disease-Modifying Drugs for Rheumatoid Arthritis

Shirinsky, I.; Shirinsky, V.

doi:10.1155/2011/937843

Cited by 16 publications

(12 citation statements)

References 44 publications

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“…In RA, a major source of M1 cytokines (TNF-α, IL-1β, IL-12p70) (50) in the joints are the synovial macrophages, whose number correlate with the inflammatory disease activity (51). On this basis, PPARδ and PPARγ are considered potential disease-modifying drugs for RA (52,53). In a murine model of experimental colitis, recruitment of CCL11-expressing Ly6C hi CCR2 + inflammatory monocytes into the colon correlates with eosinophil infiltration and histopathology (54).…”

Section: Pathologymentioning

confidence: 99%

Macrophage plasticity and polarization: in vivo veritas

2012

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(Retnla, Fizz1), and chitinase 3-like 3 (Chi3l3, Ym1) (14). IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype (4,15,16). STAT-mediated activation of macrophages is regulated by members of the SOCS family. IL-4 and IFN-γ, the latter in concert with TLR stimulation, upregulate SOCS1 and SOCS3, which in turn inhibit the action of STAT1 and STAT3, respectively (17,18).Downstream of, or in parallel with, the IRF/STAT/SOCS pathway, a panel of transcription factors orchestrates polarized macrophage activation. The nuclear receptors PPARγ (19) and PPARδ (20,21) control distinct subsets of genes associated with M2 macrophage activation and oxidative metabolism (Figure 1). Interestingly, STAT6 coordinates and synergizes with both PPARγ (22) and Krüppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function (23, 24). KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation. KLF2 regulates macrophage activation by inhibiting NF-κB/ HIF-1α activities (25). IL-4 also induces c-Myc activity in human macrophages (26), which controls genes of M2 activation (Scarb1, Alox15, and Mrc1) as well as STAT6 and PPARγ activation (26).TLR engagement leads to NF-κB activation and production of inflammatory mediators (27) associated with M1 macrophages. However, NF-κB activation also activates a genetic program essential for resolution of inflammation (28) and for M2 polarization of tumor-associated macrophages (TAMs) (29). Moreover, induction of p50 NF-κB homodimers is essential for M2 polarization in vitro and in vivo (30). The hypoxia-inducible factors HIF-1α and HIF-2α are expressed differentially in M1- and M2-polarized macrophages (31) and regulate inducible NOS2 (M1) and arginase 1 (M2), respectively. Figure 1Mechanisms of macrophage polarization. The major pathways of macrophage polarization are outlined. The crosstalk between the M1-M2 macrophage-polarizing pathways is also indicated. The balance between activation of STAT1 and STAT3/STAT6 finely regulates macrophage polarization and activity. A predominance of NF-κB and STAT1 activation promotes M1 macrophage polarization, resulting in cytotoxic and inflammatory functions. In contrast, a predominance of STAT3 and STAT6 activation results in M2 macrophage polarization, associated with immune suppression and tumor progression. PPARγ and PPARδ control distinct aspects of M2 macrophage activation and oxidative metabolism. KLF4 and KLF2 participate in the promotion of M2 macrophage functions by cooperating with STAT6 and suppressing the NF-κB/HIF-1α-dependent transcription, respectively. IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing Jmjd3-IRF4 axis to inhibit IRF5-mediated M1 polarization. IL-10 promotes M2 polarization through the induction of p50 NF-κB homodimer, c-Maf, and STAT3 activities. Epigenetic ...

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Section: Pathologymentioning

confidence: 99%

Macrophage plasticity and polarization: in vivo veritas

2012

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“…PPARα can be activated by endogenous ligands (fatty acids) and pharmacological agents (such fibrates) (Table 1) [10]. Experimental studies [15][16][17] have shown that the degradation by oxidation of proinflammatory molecules such as LTB4 (ligand of PPARα) or arachidonic acid is enhanced after PPARα stimulation. In animal models, in gene-modified mice PPARα -/-, it was detected a prolonged inflammatory response and these data are related to lack of degradations of chemotactic inflammatory eicosanoids LTB4 [16,17].…”

Section: Ppar Alpha In Chronic Inflammations and Diseasesmentioning

confidence: 99%

“…Experimental studies [15][16][17] have shown that the degradation by oxidation of proinflammatory molecules such as LTB4 (ligand of PPARα) or arachidonic acid is enhanced after PPARα stimulation. In animal models, in gene-modified mice PPARα -/-, it was detected a prolonged inflammatory response and these data are related to lack of degradations of chemotactic inflammatory eicosanoids LTB4 [16,17]. Furthermore, in wild-type mice, but not in PPARα -/mice, treatment with WY-14643, a ligand of PPARα, suppressed a number of acute phase genes such as fibrinogen, serum amyloid Pcomponent, lipocalin 2, serum amyloid A-2, metallothioneins [15,17].…”

Section: Ppar Alpha In Chronic Inflammations and Diseasesmentioning

confidence: 99%

“…In human cells, it was shown that activators of PPARα inhibit the expression of vascular cell adhesion molecule-1 (VCAM-1) gene in endothelial cells, while. In human aortic muscle cells, the nuclear receptors decrease interleukin-1 (IL-1) and induce the production of interleukine-6 (IL-6), prostaglandins and the expression of cyclooxygenase-2 (COX-2) gene [17,20]. In vivo, in patients with dyslipidemia and metabolic syndrome, treatment with fibrates decreases the circulating level of systemic inflammations markers, such as high-sensitivity C-reactive protein (hsCRP), IL-6 [15,17,19].…”

Section: Ppar Alpha In Chronic Inflammations and Diseasesmentioning

confidence: 99%

“…Figure 2. The anti-inflammatory effects of PPAR ligands -adapted from Shirinsky (2011) is mediated via NF-κB through following mechanisms [15,17]: -downregulation of the expression of signal transducing receptor components -induction of Ik-B expression -inhibition of nuclear factor kB into nucleus -decreasing of transcription factor expression levels -interference with activation of the transcription initiation complex via cofactor interaction.…”

Section: Ijppe Volume 12mentioning

confidence: 99%

See 2 more Smart Citations

Peroxisome Proliferator-Activated Receptors - Alpha in Chronic Inflammation - Mini-Review

Popa

Zugun‐Eloae

Zlei

et al. 2019

IJPPE

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The pathogeny of the metabolic syndrome (MetS) is not fully elucidated, but a link between visceral obesity and the increase of the proinflammatory response was proven. Atherosclerosis, perceived as a metabolic complication, draws attention to the peroxisome proliferator-activated receptors-alpha (PPARα). PPARα receptors are transcription factors involved in lipid metabolism, inflammation and atheromatosis. Hence, it interferes in the pathogeny of cardiovascular diseases and other chronic diseases too (neurological, psychical, neoplasical). The study of the expression of PPARα and its modulation on different level may be beneficial in the treatment of metabolic syndrome, intervening in the modulation of another proinflammatory factors. PPAR -Mechanism of ActionThe peroxisome proliferator-activated receptors (PPAR), which comprise three PPAR isoform: PPARα, PPARγ and PPARδ (10), act as transcription factors, belonging to the nuclear receptor superfamily [4-6], The mechanism of action of PPARα (Fig. 1) is similar to that of other nuclear receptors (thyroid or that of vitamin D) [7][8][9]11]. The activation of the PPAR receptor determines a change in the structure of the receptor complex, followed by changes in the expression of coded genes. PPAR acts as a ligand-activated transcription factor [7,12].

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The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study

Shirinsky¹,

Polovnikova²,

Kalinovskaya³

et al. 2012

Rheumatol Int

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Peroxisome proliferator-activated receptors α (PPARα) agonists, or fibrates, are used in the treatment for dyslipidemia. Experimental data suggest that fibrates have anti-inflammatory properties, and PPARα is essential for the differentiation of endothelial progenitor cells (EPC) which diminished pool in rheumatoid arthritis (RA) contributes to accelerated atherosclerosis. The data on fibrates' effects in patients with RA are limited. The aim of this study was to investigate changes in disease activity, inflammatory markers, lipid profile, and circulating EPC in active RA patients treated with fenofibrate. Twenty-seven patients with active RA taking traditional disease-modifying antirheumatic drugs (DMARDs) were prescribed fenofibrate (145 mg/day) for 3 months. All patients received background traditional DMARDs in stable doses. The outcomes measured were clinical disease activity variables, circulating cytokines, adipokines, lipids, and EPC. Twenty-five patients completed the study. At the end of treatment, there was a significant reduction in DAS28, all individual DAS28 components except tender joint count, the duration of morning stiffness, and in the patient's assessment of disease activity. Fifteen (60 %) patients achieved good/moderate EULAR response, while 10 (40 %) patients satisfied ACR20 response criteria. Treatment with fenofibrate resulted in significant decrease in CRP and IL-6 concentrations and improvement in lipid profile. There was no change in the concentrations of circulating EPC. In conclusion, fenofibrate treatment is associated with reduced inflammation and improved lipid profile in RA patients. Large randomized controlled studies are needed to confirm these results and to define the role of fibrates in the treatment for RA.

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Targeting Nuclear Hormone Receptors: PPARαAgonists as Potential Disease-Modifying Drugs for Rheumatoid Arthritis

Cited by 16 publications

References 44 publications

Macrophage plasticity and polarization: in vivo veritas

Macrophage plasticity and polarization: in vivo veritas

Peroxisome Proliferator-Activated Receptors - Alpha in Chronic Inflammation - Mini-Review

The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study

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