scholarly journals Peroxisome proliferator-activated receptor α and γ agonists differently regulate classical and alternative macrophage activation

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Erja-Leena Paukkeri ◽  
Antti Pekurinen ◽  
Eeva Moilanen
Keyword(s):  
Macrophage Activation ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Alternative Activation ◽  
Peroxisome Proliferator ◽  
Activation Markers ◽  
Peroxisome Proliferator Activated Receptor ◽  
Arginase 1 ◽  
Pparγ Agonist ◽  
Ppar Agonists

AbstractPeroxisome proliferator-activated receptor (PPAR) agonists, fibrates and thiazolidinediones, are commonly used drugs in the treatment of dyslipidemia and diabetes. Their targets, PPARα and PPARγ, have also been shown to have a role in the regulation of inflammatory responses linking metabolism and inflammation. In the present study we investigated the effects of PPAR agonists on macrophage activation. In addition to the proinflammatory classical activation, we also focused on interleukin (IL) 4 and 13 -induced alternative activation which is a significant macrophage phenotype in tissue repairing processes and in fibrosing diseases. PPARα agonists GW7647 and fenofibrate as well as PPARγ agonist GW1929 inhibited lipopolysaccharide-induced classical macrophage activation and production of the characteristic biomarkers of this phenotype, i.e. IL-6 and nitric oxide, in murine J774 macrophages. Remarkably, the PPARα agonists also inhibited IL-4 and IL-13 –induced expression of alternative activation markers arginase-1, fizz1 and mannose receptor 1 whereas the PPARγ agonist GW1929 enhanced their expression in J774 macrophages. The PPARα agonists GW7647 and fenofibrate also attenuated the production of alternative activation markers chemokine (C-C motif) ligand 13 and plateletderived growth factor in human THP-1 macrophages. The present findings show that PPARα and PPARγ agonists differently regulate classical and alternative macrophage phenotypes. Furthermore, PPARα activation was introduced as a novel concept to down-regulate alternative macrophage activation indicating that PPARα agonists have therapeutic potential in conditions associated with aberrant alternative macrophage activation such as fibrosing diseases.

scholarly journals Dexamethasone promotes IL-4-induced alternative activation at PPARγ point, instead of upstream STAT6 in BV2 microglial cells

2020 ◽  
Author(s):  
Zongfeng Chen ◽  
Liang Zhang ◽  
Xin Xue ◽  
Peng Liu ◽  
Xiang Yin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Polarization State ◽  
Microglial Cells ◽  
Alternative Activation ◽  
Peroxisome Proliferator ◽  
Activation Markers ◽  
Arginase 1 ◽  
The Central Nervous System

Abstract Background Microglia are innate immune effector cells in the central nervous system and play an extremely important role in the physiological processes of the central nervous system. When microglia are activated, there are two polarization states, M1 and M2 phenotype. Dexamethasone is a glucocorticoid widely used in clinical practice, which pharmacological effects are mainly anti-inflammatory, anti-toxic. However, whether Dexamethasone affects polarization state of microglia is unknown. In this study, we investigate the effect of Dexamethasone on IL-4-induced alternative activation in murine BV-2 microglial cells. Methods BV-2 cells were incubated with Dexamethasone alone, IL-4 alone, or the combination of Dexamethasone and IL-4. Western blot and immunofluorescence were performed to detect protein levels of alternative activation markers arginase 1 (Arg1), found in inflammatory zone 1 (FIZZ1). Moreover, we investigated the effects of Dexamethasone on IL-4 induced activation of signal transducer and activators of transcription 6 (STAT6) and peroxisome proliferator-activated receptor-gamma (PPARγ). Results Dexamethasone promoted IL-4 induced microglia alternative activation by increasing the expression of Arg1 and FIZZ1. Dexamethasone also enhanced the expression of PPARγ. These effects were reversed by RU486 (a Dexamethasone antagonist). Further, the effects of Dexamethasone and IL-4 on Arg1 and FIZZ1 were blocked by the application of GW9662 (a PPARγ antagonist). Conclusions Our studies confirm that Dexamethasone promotes IL-4 induced alternative activation via STAT6/PPARγ signaling pathways in microglia. At the same time, it was confirmed that Dexamethasone acts on PPARγ instead of STAT6. These findings support that Dexamethasone has a therapeutic potential for neuroinflammatory diseases via alternative activation.

scholarly journals PPARγ and TGFβ—Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys

2021 ◽  
Vol 22 (19) ◽  
pp. 10431
Author(s):  
Gábor Kökény ◽  
Laurent Calvier ◽  
Georg Hansmann
Keyword(s):  
Transforming Growth Factor Beta ◽  
Kidney Failure ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Biological Effects ◽  
Critical Conditions ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.

scholarly journals Regulation of Glial Cell Functions by PPAR- Natural and Synthetic Agonists

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
Antonietta Bernardo ◽  
Luisa Minghetti
Keyword(s):  
Therapeutic Potential ◽  
Experimental Models ◽  
Brain Inflammation ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Functions ◽  
Parkinson’S Diseases ◽  
Ppar Agonists ◽  
Anti Inflammatory

In the recent years, the peroxisome proliferator-activated receptor- (PPAR-), a well known target for type II diabetes treatment, has received an increasing attention for its therapeutic potential in inflammatory and degenerative brain disorders. PPAR- agonists, which include naturally occurring compounds (such as long chain fatty acids and the cyclopentenone prostaglandin 15-deoxy prostaglandin ), and synthetic agonists (among which the thiazolidinediones and few nonsteroidal anti-inflammatory drugs) have shown anti-inflammatory and protective effects in several experimental models of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis and stroke, as well as in few clinical studies. The pleiotropic effects of PPAR- agonists are likely to be mediated by several mechanisms involving anti-inflammatory activities on peripheral immune cells (macrophages and lymphocytes), as well as direct effects on neural cells including cerebral vascular endothelial cells, neurons, and glia. In the present article, we will review the recent findings supporting a major role for PPAR- agonists in controlling neuroinflammation and neurodegeneration through their activities on glial cells, with a particular emphasis on microglial cells as major macrophage population of the brain parenchyma and main actors in brain inflammation.

scholarly journals PPARγ in Placental Angiogenesis

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4969-4981 ◽  
Author(s):  
Karim Nadra ◽  
Laure Quignodon ◽  
Chiara Sardella ◽  
Elisabeth Joye ◽  
Antonio Mucciolo ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Late Pregnancy ◽  
Peroxisome Proliferator ◽  
Placental Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Placental Angiogenesis ◽  
Pparγ Agonist ◽  
Vascular Proliferation ◽  
Knockout Animals ◽  
Endothelial Growth Factor

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in diverse biological processes including adipocyte differentiation, glucose homeostasis, and inflammatory responses. Analyses of PPARγ knockout animals have been so far preempted by the early embryonic death of PPARγ−/− embryos as a consequence of the severe alteration of their placental vasculature. Using Sox2Cre/PPARγL2/L2 mice, we obtained fully viable PPARγ-null mice through specific and total epiblastic gene deletion, thereby demonstrating that the placental defect is the unique cause of PPARγ−/− embryonic lethality. The vasculature defects observed in PPARγ−/− placentas at embryonic d 9.5 correlated with an unsettled balance of pro- and antiangiogenic factors as demonstrated by increased levels of proliferin (Prl2c2, PLF) and decreased levels of proliferin-related protein (Prl7d1, PRP), respectively. To analyze the role of PPARγ in the later stage of placental development, when its expression peaks, we treated pregnant wild-type mice with the PPARγ agonist rosiglitazone. This treatment resulted in a disorganization of the placental layers and an altered placental microvasculature, accompanied by the decreased expression of proangiogenic genes such as Prl2c2, vascular endothelial growth factor, and Pecam1. Together our data demonstrate that PPARγ plays a pivotal role in controlling placental vascular proliferation and contributes to its termination in late pregnancy.

Ciglitazone Inhibits Plasmin-Induced Proinflammatory Monocyte Activation via Modulation of p38 MAP Kinase Activity

2002 ◽  
Vol 88 (08) ◽  
pp. 274-281 ◽  
Author(s):  
Tatiana Syrovets ◽  
Almut Schüle ◽  
Marina Jendrach ◽  
Berthold Büchele ◽  
Thomas Simmet
Keyword(s):  
Gene Activation ◽  
P38 Map Kinase ◽  
Clofibric Acid ◽  
Peroxisome Proliferator ◽  
Surface Plasmon Resonance Analysis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Pparγ Agonist ◽  
Tnf Α ◽  
Ppar Agonists

SummaryPlasmin triggers chemotaxis and NF-κBand AP-1-mediated proinflammatory gene expression in human peripheral monocytes (PM). Compared with macrophages and dendritic cells, PM express mainly the peroxisome proliferator-activated receptor (PPAR) γ and traces of PPARα as detected by semiquantitative RT-PCR and immunoblotting. The PPARγ agonist ciglitazone, but not the PPARα agonist clofibric acid, concentration-dependently inhibited the plasmin-, but not the FMLP-induced PM chemotaxis. Similarly, release of interleukin (IL)-1α, IL-1β and tumor necrosis factor (TNF)-α from plasmin-stimulated PM was concentration-dependently inhibited by ciglitazone, but not by clofibric acid, while the LPS-induced TNF-α release remained unaffected by any of both PPAR agonists. Ciglitazone activates PPARγ as shown by a novel surface plasmon resonance analysis and inhibits the plasmin-induced activation of NF-κB and AP-1. It also inhibits p38 MAPK phosphorylation essential for the plasmin-induced PM chemotaxis and gene activation. Thus, activation of PPARγ by ciglitazone may allow controling of the plasmin-mediated recruitment and activation of PM at sites of inflammation.

scholarly journals Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate

2008 ◽  
Vol 417 (1) ◽  
pp. 223-238 ◽  
Author(s):  
Ana M. Ferreira ◽  
Mariana I. Ferrari ◽  
Andrés Trostchansky ◽  
Carlos Batthyany ◽  
José M. Souza ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Macrophage Activation ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inflammatory Stimuli ◽  
Anti Inflammatory ◽  
Electrophilic Reactivity

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPARγ (peroxisome-proliferator-activated receptor γ) ligand activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present study, we show increased nitration of cholesteryl-linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase ∼20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-γ; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the •NO (nitric oxide) inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPARγ and •NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-κB (nuclear factor κB) activation. Overall, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.

scholarly journals PPAR γ agonist, pioglitazone, suppresses melanoma cancer in mice by inhibiting TLR4 signaling

2019 ◽  
Vol 22 ◽  
pp. 418-423 ◽  
Author(s):  
Nasim Dana ◽  
Golnaz Vaseghi ◽  
Shaghayegh Haghjooy javanmard
Keyword(s):  
Protein Expression ◽  
Cancer Progression ◽  
Tumor Volume ◽  
Inflammatory Responses ◽  
Melanoma Cells ◽  
Peroxisome Proliferator ◽  
Melanoma Tumor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist ◽  
Tnf Α

Background:  Although previous studies demonstrated an anticancer effect for the ligands of peroxisome proliferator-activated receptor gamma (PPARγ) through activation of its anti-inflammatory responses, nevertheless the anti-tumor mechanism of PPARγ has not been intensively investigated. One of the molecules involved in cancer progression is toll-like receptor 4 (TLR4).Methods: B16F10 melanoma cells were cultured with or without LPS for 24 hr. The cells were subcutaneously injected to two groups of C57BL/6 mice. After the development of palpable tumors each group of animals were divide to four sub-groups and received pioglitazone in different dose ranges (0,10,50,100 mg/kg/day) for 10 days. At the end of the study, the expression of Tlr4, Myd-88, Nf-kb1 genes was evaluated by qRT-PCR in different groups in mice tumor. The TLR-4 protein expression was evaluated by IHC. TNF-α level in mice tumor and serum were measured by ELISA kits. Tumor volume was measured with Vernier calipers.Results: We observed that activation of PPARγ by its agonist, pioglitazone, reduces tumor volume, Tlr-4, Myd-88, Nf-kb1 mRNA expression, TLR4 protein expression and TNF-α production in melanoma tumor especially in groups that were injected with LPS –stimulated cells. Moreover, treatment of melanoma cells with pioglitazone showed that the inhibitory effects of pioglitazone on LPS-induced inflammatory responses were TLR4 dependent.Conclusions: The results indicate that pioglitazone, a PPARγ agonist, has a beneficial protective effect against melanoma via interfering with the TLR4-dependent signaling pathways.

scholarly journals MicroRNA-511-3p Mediated Modulation of the Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Controls LPS-Induced Inflammatory Responses in Human Monocyte Derived DCs

Immuno ◽  
2022 ◽  
Vol 2 (1) ◽  
pp. 104-117
Author(s):  
Dennis Awuah ◽  
Alisa Ruisinger ◽  
Meshal Alobaid ◽  
Chidimma Mbadugha ◽  
Amir M. Ghaemmaghami
Keyword(s):  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Human Monocyte ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inflammatory Cytokine Production ◽  
Pparγ Agonist ◽  
And Function ◽  
First Time

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor expressed in dendritic cells (DCs), where it exerts anti-inflammatory responses against TLR4-induced inflammation. Recently, microRNA-511 (miR-511) has also emerged as a key player in controlling TLR4-mediated signalling and in regulating the function of DCs. Interestingly, PPARγ has been previously highlighted as a putative target of miR-511 activity; however, the link between miR-511 and PPARγ and its influence on human DC function within the context of LPS-induced inflammatory responses is unknown. Using a selection of miR-511-3p-specific inhibitors and mimics, we demonstrate for the first time that knockdown or overexpression of miR-511-3p inversely correlates with PPARγ mRNA levels and affects its transcriptional activity following treatment with rosiglitazone (RSG; PPARγ agonist), in the presence or absence of LPS. Additionally, we show that PPARγ-mediated suppression of DC activation and pro-inflammatory cytokine production in miR-511-3p knockdown DCs is abrogated following overexpression of miR-511-3p. Lastly, PPARγ activation suppressed LPS-mediated induction of indoleamine 2,3-dioxygenase (IDO) activity in DCs, most likely due to changes in miR-511-3p expression. Our data thus suggests that PPARγ-induced modulation of DC phenotype and function is influenced by miR-511-3p expression, which may serve as a potential therapeutic target against inflammatory diseases.

scholarly journals BST204 Protects Dexamethasone-Induced Myotube Atrophy through the Upregulation of Myotube Formation and Mitochondrial Function

2021 ◽  
Vol 18 (5) ◽  
pp. 2367
Author(s):  
Ryuni Kim ◽  
Hyebeen Kim ◽  
Minju Im ◽  
Sun Kyu Park ◽  
Hae Jung Han ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Inflammatory Responses ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dry Extract ◽  
Myotube Formation ◽  
Species Production

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.

scholarly journals Arginase in Parasitic Infections: Macrophage Activation, Immunosuppression, and Intracellular Signals

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Cinthia C. Stempin ◽  
Laura R. Dulgerian ◽  
Vanina V. Garrido ◽  
Fabio M. Cerban
Keyword(s):  
Macrophage Activation ◽  
Transforming Growth Factor ◽  
Parasite Clearance ◽  
Alternative Activation ◽  
Parasitic Infections ◽  
Activated Macrophages ◽  
Proinflammatory Response ◽  
Alternatively Activated Macrophages ◽  
Arginase 1

A type 1 cytokine-dependent proinflammatory response inducing classically activated macrophages (CaMϕs) is crucial for parasite control during protozoan infections but can also contribute to the development of immunopathological disease symptoms. Type 2 cytokines such as IL-4 and IL-13 antagonize CaMϕs inducing alternatively activated macrophages (AaMϕs) that upregulate arginase-1 expression. During several infections, induction of arginase-1-macrophages was showed to have a detrimental role by limiting CaMϕ-dependent parasite clearance and promoting parasite proliferation. Additionally, the role of arginase-1 in T cell suppression has been explored recently. Arginase-1 can also be induced by IL-10 and transforming growth factor-β(TGF-β) or even directly by parasites or parasite components. Therefore, generation of alternative activation states of macrophages could limit collateral tissue damage because of excessive type 1 inflammation. However, they affect disease outcome by promoting parasite survival and proliferation. Thus, modulation of macrophage activation may be instrumental in allowing parasite persistence and long-term host survival.

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