Peroxisome proliferator-activated receptor-γ agonists suppress iNOS expression induced by LPS in rat primary Schwann cells

Zhang, Fupeng; Liu, Fen; Yan, Ming; Ji, Huoyan; Hu, Ling; Li, Xiaohong; Qian, Ji; He, Xing; Zhang, Li; Shen, Aiguo; Cheng, Chun

doi:10.1016/j.jneuroim.2009.10.016

Cited by 23 publications

(20 citation statements)

References 71 publications

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“…However, this observation regarding the potential stimulation of TLR4 expression by 15d-PGJ 2 needs to be interpreted with caution, since 15d-PGJ 2 does not exhibit any regulatory effect on TLR4 expression in the absence of LPS [34]. Of note, several lines of evidence suggest that 15d-PGJ 2 is capable of suppressing TLR4 expression in different cell lines, such as mouse T lymphocytes [35], rat Schwann cells [36] and human intestinal epithelial cells [33].…”

Section: Discussionmentioning

confidence: 97%

Interleukin-6 Synthesis in Human Chondrocytes Is Regulated via the Antagonistic Actions of Prostaglandin (PG)E2 and 15-deoxy-Δ12,14-PGJ2

2011

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BackgroundElevated levels of interleukin-6 (IL-6), prostaglandin (PG)E2, PGD2 and its dehydration end product 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) have been detected in joint synovial fluids from patients with rheumatoid arthritis (RA). PGE2 directly stimulates IL-6 production in human articular chondrocytes. However, the effects of PGD2 and 15d-PGJ2 in the absence or presence of PGE2 on IL-6 synthesis in human chondrocytes have yet to be determined. It is believed that dysregulated overproduction of IL-6 is responsible for the systemic inflammatory manifestations and abnormal laboratory findings in RA patients.Methodology/Principal FindingsUsing the T/C-28a2 chondrocyte cell line as a model system, we report that exogenous PGE2 and PGD2/15d-PGJ2 exert antagonistic effects on IL-6 synthesis in human T/C-28a2 chondrocytes. Using a synthesis of sophisticated molecular biology techniques, we determined that PGE2 stimulates Toll-like receptor 4 (TLR4) synthesis, which is in turn responsible for the activation of the ERK1/2, PI3K/Akt and PKA/CREB pathways that phosphorylate the NF-κB p65 subunit leading to NF-κB activation. Binding of the activated NF-κB p65 subunit to IL-6 promoter induces IL-6 synthesis in human T/C28a2 chondrocytes. PGD2 or 15d-PGJ2 concurrently downregulates TLR4 and upregulates caveolin-1, which in turn inhibit the PGE2-dependent ERK1/2, PI3-K and PKA activation, and ultimately with NF-κB-dependent IL-6 synthesis in chondrocytes.Conclusions/SignificanceWe have delineated the signaling cascade by which PGE2 and PGD2/15d-PGJ2 exert opposing effects on IL-6 synthesis in human chondrocytes. Elucidation of the molecular pathway of IL-6 synthesis and secretion by chondrocytes will provide insights for developing strategies to reduce inflammation and pain in RA patients.

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Section: Discussionmentioning

confidence: 97%

Interleukin-6 Synthesis in Human Chondrocytes Is Regulated via the Antagonistic Actions of Prostaglandin (PG)E2 and 15-deoxy-Δ12,14-PGJ2

2011

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“…The reconstitution system we have established, allows a direct and extensive comparison of the responses of TLR4 to LPS. Numerous studies have indicated ameliorating properties of PPARc in LPS-induced inflammatory conditions in a variety of cells (Zhang et al 2010 andJung et al 2012;Ji et al 2009 andZhao et al 2011;Wang et al 2011;Necela et al 2008;Yin et al 2013Yin et al , 2014. To clarify whether anti-inflammatory effects of PPARc are mediated via TLR4 receptor inhibition, we implemented such reporter cell.…”

Section: Discussionmentioning

confidence: 99%

“…Peroxisome proliferator-activated receptor-gamma (PPARc) is a ligand-activated transcription factor with numerous biological effects. It also exerts a potential anti-inflammatory effect by suppressing TLR4-mediated inflammation Jung et al 2012;Ji et al 2011;Zhao et al 2011;Wang et al 2011;Zhang et al 2010;Ji et al 2009;Necela et al 2008;Yin et al 2013Yin et al , 2014.…”

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confidence: 99%

PPARγ ameliorated LPS induced inflammation of HEK cell line expressing both human Toll-like receptor 4 (TLR4) and MD2

et al. 2015

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TLR4 is transmembrane pattern-recognition receptor that initiates signals in response to diverse pathogen-associated molecular patterns especially LPS. Recently, there have been an increasing number of studies about the role of TLRs in the pathogenesis of several disorders as well as the therapeutic potential of TLR intervention in such diseases. Peroxisome proliferator-activated receptorgamma (PPARc) is a ligand-activated transcription factor with numerous biological effects. PPARc has been shown to exert a potential anti-inflammatory effect through suppression of TLR4-mediated inflammation. Therefore, PPARc agonists may have a potential to combat inflammatory conditions in pathologic states. The current study aims to show the decrease of inflammation by overexpression of PPARc in a cell reporter model. To reach this goal, recombinant pBudCE4.1 (?) containing encoding sequences of human TLR4 and MD2 was constructed and used to transfect HEK cells. Subsequently, inflammation was induced by LPS treatment as control group. In the treatment group, overexpression of PPARc prior to inflammation was performed and the expression of inflammatory markers was assessed in this condition. The expression of inflammatory markers (TNFa and iNOS) was defined by quantitative real time PCR and the amount of phosphorylated NF-jB was measured by western blot. Data indicated expression of TNFa and iNOS increased in LPS induced inflammation of stably transformed HEK cells with MD2 and TLR4. In this cell reporter model overexpression of PPARc dramatically prevented LPSinduced inflammation through the blocking of TLR4/ NF-jB signaling. PPARc was shown to negatively regulate TLR4 activity and therefore exerts its antiinflammatory action against LPS induced inflammation.

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“…15-Deoxy-Δ12,14-prostaglandin J 2 (15d-PGJ 2 ) is the ultimate metabolite of PGD 2 through spontaneous nonenzymatic dehydration followed by isomerization and is an endogenous ligand for PPARγ [13]. 15D-PGJ 2 possesses anti-inflammatory properties and plays a protective role in CNS injury [14–16]. It has been reported that anti-inflammatory macrophages could release 15d-PGJ 2 [17–19] and that 15d-PGJ 2 could promote the proliferation of NSPCs via the PPARγ pathway [20].…”

Section: Introductionmentioning

confidence: 99%

M2 microglia promotes neurogenesis and oligodendrogenesis from neural stem/progenitor cells via the PPARγ signaling pathway

Yuan

Liu

et al. 2017

Oncotarget

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Neural stem/progenitor cells (NSPCs) are an important source of cells for cell replacement therapy after nerve injury. How to induce NSPCs differentiation towards neurons and oligodendrocytes is a challenging issue in neuroscience research. In the present study, we polarized microglia into M1 and M2 phenotype, used their supernatants to induce NSPCs differentiation, and investigated the effects of different microglia phenotypes on NSPCs differentiation and their mechanisms. We discovered that, after exposure to M1 phenotype supernatant, NSPCs differentiated into fewer Tuj-1+ and Olig2+ cells, but more GFAP+ cells. Meanwhile, a significantly increased number of Tuj-1+ and Olig2+ cells and smaller number of GFAP+ cells were generated by M2 microglia supernatant-induced NSPCs differentiation. We also observed that 15d-PGJ2, an endogenous ligand of PPARγ, was elevated in M2 phenotype supernatant and could activate PPARγ expression in NSPCs, whereas use of the PPARγ inhibitor GW9662, could reduce the percentage of differentiated neurons and oligodendrocytes. Our study results confirm that M2 microglia supernatant can activate the PPARγ signaling pathway and promote neurogenesis and oligodendrogenesis from NSPCs differentiation. The present study provides a further theoretical basis for induction of NSPCs oriented differentiation.

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Peroxisome proliferator-activated receptor-γ agonists suppress iNOS expression induced by LPS in rat primary Schwann cells

Cited by 23 publications

References 71 publications

Interleukin-6 Synthesis in Human Chondrocytes Is Regulated via the Antagonistic Actions of Prostaglandin (PG)E2 and 15-deoxy-Δ12,14-PGJ2

Interleukin-6 Synthesis in Human Chondrocytes Is Regulated via the Antagonistic Actions of Prostaglandin (PG)E2 and 15-deoxy-Δ12,14-PGJ2

PPARγ ameliorated LPS induced inflammation of HEK cell line expressing both human Toll-like receptor 4 (TLR4) and MD2

M2 microglia promotes neurogenesis and oligodendrogenesis from neural stem/progenitor cells via the PPARγ signaling pathway

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