scholarly journals Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity

2007 ◽  
Vol 204 (2) ◽  
pp. 321-330 ◽  
Author(s):  
Shannon E. Dunn ◽  
Shalina S. Ousman ◽  
Raymond A. Sobel ◽  
Luis Zuniga ◽  
Sergio E. Baranzini ◽  
...  
Keyword(s):  
Gender Differences ◽  
T Cell ◽  
Inflammatory Responses ◽  
Clinical Signs ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Genetic Ablation

Peroxisome proliferator–activated receptor (PPAR)α is a nuclear receptor that mediates gender differences in lipid metabolism. PPARα also functions to control inflammatory responses by repressing the activity of nuclear factor κB (NF-κB) and c-jun in immune cells. Because PPARα is situated at the crossroads of gender and immune regulation, we hypothesized that this gene may mediate sex differences in the development of T cell–mediated autoimmune disease. We show that PPARα is more abundant in male as compared with female CD4+ cells and that its expression is sensitive to androgen levels. Genetic ablation of this gene selectively removed the brake on NF-κB and c-jun activity in male T lymphocytes, resulting in higher production of interferon γ and tumor necrosis factor (but not interleukin 17), and lower production of T helper (Th)2 cytokines. Upon induction of experimental autoimmune encephalomyelitis, male but not female PPARα−/− mice developed more severe clinical signs that were restricted to the acute phase of disease. These results suggest that males are less prone to develop Th1-mediated autoimmunity because they have higher T cell expression of PPARα.

Regulation of dectin-1–mediated dendritic cell activation by peroxisome proliferator–activated receptor-gamma ligand troglitazone

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3569-3574 ◽  
Author(s):  
Grethe Kock ◽  
Anita Bringmann ◽  
Stefanie Andrea Erika Held ◽  
Solveig Daecke ◽  
Annkristin Heine ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Mitogen Activated Protein

Abstract Dectin-1 is the major receptor for fungal β-glucans. The activation of Dectin-1 leads to the up-regulation of surface molecules on dendritic cells (DCs) and cytokine secretion. Furthermore, Dectin-1 is important for the recruitment of leukocytes and the production of inflammatory mediators. Peroxisome proliferator–activated receptor-γ (PPAR-γ) and its ligands, cyclopentenone prostaglandins or thiazolidinediones, have modulatory effects on B-cell, T-cell, and DC function. In the present study, we analyzed the effects of troglitazone (TGZ), a high-affinity synthetic PPAR-γ ligand, on the Dectin-1–mediated activation of monocyte-derived human DCs. Dectin-1–mediated activation of DCs was inhibited by TGZ, as shown by down-regulation of costimulatory molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation. Furthermore, TGZ inhibited the T-cell–stimulatory capacity of DCs. These effects were not due to a diminished expression of Dectin-1 or to a reduced phosphorylation of spleen tyrosine kinase; they were mediated by the inhibition of downstream signaling molecules such as mitogen-activated protein kinases and nuclear factor-κB. Furthermore, curdlan-mediated accumulation of caspase recruitment domain 9 (CARD9) in the cytosol was inhibited by TGZ. Our data demonstrate that the PPAR-γ ligand TGZ inhibits Dectin-1–mediated activation by interfering with CARD9, mitogen-activated protein kinase, and nuclear factor-κB signaling pathways. This confirms their important role as negative-feedback regulators of potentially harmful inflammatory responses.

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 Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity

2007 ◽  
Vol 176 (4) ◽  
pp. i9-i9
Author(s):  
Shannon E. Dunn ◽  
Shalina S. Ousman ◽  
Raymond A. Sobel ◽  
Luis Zuniga ◽  
Sergio E. Baranzini ◽  
...  
Keyword(s):  
Gender Differences ◽  
T Cells ◽  
T Cell ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Attenuation of Colon Inflammation through Activators of the Retinoid X Receptor (Rxr)/Peroxisome Proliferator–Activated Receptor γ (Pparγ) Heterodimer

2001 ◽  
Vol 193 (7) ◽  
pp. 827-838 ◽  
Author(s):  
Pierre Desreumaux ◽  
Laurent Dubuquoy ◽  
Sophie Nutten ◽  
Michel Peuchmaur ◽  
Walter Englaro ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Synergistic Effects ◽  
Survival Rates ◽  
Nuclear Factor Κb ◽  
Retinoid X Receptor ◽  
Trinitrobenzene Sulfonic Acid ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Colon Inflammation

The peroxisome proliferator–activated receptor γ (PPARγ) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARγ and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARγ1/− and RXRα1/− mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARγ heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARγ agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARγ and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor α and interleukin 1β mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor κB DNA binding activity, c-Jun NH2-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARγ and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARγ heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARγ ligands might hold promise in the clinic due to their synergistic effects.

scholarly journals Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity

2007 ◽  
Vol 204 (3) ◽  
pp. 693-693
Author(s):  
Shannon E. Dunn ◽  
Shalina S. Ousman ◽  
Raymond A. Sobel ◽  
Luis Zuniga ◽  
Sergio E. Baranzini ◽  
...  
Keyword(s):  
Gender Differences ◽  
T Cells ◽  
T Cell ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Adiponectin inhibits LPS-induced NF-κB activation and IL-6 production and increases PPARγ2 expression in adipocytes

2005 ◽  
Vol 288 (5) ◽  
pp. R1220-R1225 ◽  
Author(s):  
Kolapo M. Ajuwon ◽  
Michael E. Spurlock
Keyword(s):  
Adipose Tissue ◽  
Culture Media ◽  
Elevated Serum ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aortic Endothelial Cells ◽  
Nuclear Extracts ◽  
Tnf Α

Obesity and insulin resistance are often associated with lower circulating adiponectin concentrations and elevated serum interleukin-6 (IL-6) and/or tumor necrosis factor-α (TNF-α). Adiponectin suppresses activation of nuclear factor-κB (NF-κB) in aortic endothelial cells and porcine macrophages. Accordingly, we hypothesized that adiponectin is an anti-inflammatory hormone and suppresses activation of NF-κB in adipocytes. Because peroxisome proliferator-activated receptor γ2 (PPARγ2) antagonizes the transcriptional activity of NF-κB, we determined whether adiponectin alters PPARγ2 expression in pig adipocytes. In addition, we determined whether interferon-γ alters the expression of PPARγ2 in the presence or absence of adiponectin. Primary adipocytes from pig subcutaneous adipose tissue were treated with or without lipopolysaccharide (LPS; 10 μg/ml) and adiponectin (30 μg/ml), and nuclear extracts were obtained for gel shift assays to assess nuclear localization of NF-κB. Whereas LPS induced an increase in NF-κB activation, adiponectin suppressed both NF-κB activation and the induction of IL-6 expression by LPS ( P < 0.05). Similar results were obtained in 3T3-L1 adipocytes. In addition, adiponectin antagonized LPS-induced increase in TNF-α mRNA expression ( P < 0.05) and tended ( P < 0.065) to diminish its accumulation in the culture media in 3T3-L1 adipocytes. Adiponectin also induced an upregulation of PPARγ2 mRNA ( P < 0.05). Although IFN-γ did not reduce the basal expression of PPARγ2, it suppressed PPARγ2 induction by adiponectin ( P < 0.05). These findings indicate that adiponectin may be a local regulator of inflammation in the adipocyte and adipose tissue via its regulation of the NF-κB and PPARγ2 transcription factors.

scholarly journals The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 934
Author(s):  
Woon-Man Kung ◽  
Muh-Shi Lin
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Management Strategies ◽  
Nuclear Factor Κb ◽  
Peroxisome Proliferator ◽  
Proinflammatory Response ◽  
Pharmacological Management ◽  
Peroxisome Proliferator Activated Receptor ◽  
Iron Sulfur ◽  
Promising Target

Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.

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