scholarly journals Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock

2007 ◽  
Vol 204 (3) ◽  
pp. 583-594 ◽  
Author(s):  
Chul-Su Yang ◽  
Dong-Seok Lee ◽  
Chang-Hwa Song ◽  
Se-Jin An ◽  
Shengjin Li ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Host Responses ◽  
Enhanced Sensitivity ◽  
Mitogen Activated Protein ◽  
Lethal Shock ◽  
Deficient Mice

Mammalian 2-Cys peroxiredoxin II (Prx II) is a cellular peroxidase that eliminates endogenous H2O2. The involvement of Prx II in the regulation of lipopolysaccharide (LPS) signaling is poorly understood. In this report, we show that LPS induces substantially enhanced inflammatory events, which include the signaling molecules nuclear factor κB and mitogen-activated protein kinase (MAPK), in Prx II–deficient macrophages. This effect of LPS was mediated by the robust up-regulation of the reactive oxygen species (ROS)–generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and the phosphorylation of p47phox. Furthermore, challenge with LPS induced greater sensitivity to LPS-induced lethal shock in Prx II–deficient mice than in wild-type mice. Intravenous injection of Prx II–deficient mice with the adenovirus-encoding Prx II gene significantly rescued mice from LPS-induced lethal shock as compared with the injection of a control virus. The administration of catalase mimicked the reversal effects of Prx II on LPS-induced inflammatory responses in Prx II–deficient cells, which suggests that intracellular H2O2 is attributable, at least in part, to the enhanced sensitivity to LPS. These results indicate that Prx II is an essential negative regulator of LPS-induced inflammatory signaling through modulation of ROS synthesis via NADPH oxidase activities and, therefore, is crucial for the prevention of excessive host responses to microbial products.

Glycyrrhizin, the main active compound in liquorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalling

2009 ◽  
Vol 421 (3) ◽  
pp. 473-482 ◽  
Author(s):  
Bärbel Schröfelbauer ◽  
Johanna Raffetseder ◽  
Maria Hauner ◽  
Andrea Wolkerstorfer ◽  
Wolfgang Ernst ◽  
...  
Keyword(s):  
Active Compound ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Raw 264.7 Cells ◽  
Cpg Dna ◽  
Cellular Attachment ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
Factor Α

The triterpene glycoside glycyrrhizin is the main active compound in liquorice. It is used as a herbal medicine owing to its anticancer, antiviral and anti-inflammatory properties. Its mode of action, however, remains widely unknown. In the present study, we aimed to elucidate the molecular mechanism of glycyrrhizin in attenuating inflammatory responses in macrophages. Using microarray analysis, we found that glycyrrhizin caused a broad block in the induction of pro-inflammatory mediators induced by the TLR (Toll-like receptor) 9 agonist CpG-DNA in RAW 264.7 cells. Furthermore, we found that glycyrrhizin also strongly attenuated inflammatory responses induced by TLR3 and TLR4 ligands. The inhibition was accompanied by decreased activation not only of the NF-κB (nuclear factor κB) pathway but also of the parallel MAPK (mitogen-activated protein kinase) signalling cascade upon stimulation with TLR9 and TLR4 agonists. Further analysis of upstream events revealed that glycyrrhizin treatment decreased cellular attachment and/or uptake of CpG-DNA and strongly impaired TLR4 internalization. Moreover, we found that the anti-inflammatory effects were specific for membrane-dependent receptor-mediated stimuli, as glycyrrhizin was ineffective in blocking Tnfa (tumour necrosis factor α gene) induction upon stimulation with PMA, a receptor- and membrane-independent stimulus. These observations suggest that the broad anti-inflammatory activity of glycyrrhizin is mediated by the interaction with the lipid bilayer, thereby attenuating receptor-mediated signalling.

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 Immunological and toxicological risk assessment of e-cigarettes

2018 ◽  
Vol 27 (147) ◽  
pp. 170119 ◽  
Author(s):  
Gagandeep Kaur ◽  
Rakeysha Pinkston ◽  
Benathel Mclemore ◽  
Waneene C. Dorsey ◽  
Sanjay Batra
Keyword(s):  
Tobacco Smoke ◽  
Prolonged Exposure ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Mitogen Activated Protein ◽  
Immunological Effects ◽  
Contradictory Evidence

Knowledge of the long-term toxicological and immunological effects of e-cigarette (e-cig) aerosols remains elusive due to the relatively short existence of vaping. Therefore, we performed a systematic search of articles published in public databases and analysed the research evidence in order to provide critical information regarding e-cig safety. Electronic nicotine delivery systems (or e-cigs) are an alternative to traditional cigarettes for the delivery of nicotine and are typically filled with glycerol or propylene glycol-based solutions known as e-liquids. Though present in lower quantities, e-cig aerosols are known to contain many of the harmful chemicals found in tobacco smoke. However, due to the paucity of experimental data and contradictory evidence, it is difficult to draw conclusive outcomes regarding toxicological, immunological and clinical impacts of e-cig aerosols. Excessive vaping has been reported to induce inflammatory responses including mitogen-activated protein kinase, Janus tyrosine kinase/signal transducer and activator of transcription and nuclear factor-κB signalling, similar to that induced by tobacco smoke. Based on recent evidence, prolonged exposure to some constituents of e-cig aerosols might result in respiratory complications such as asthma, chronic obstructive pulmonary disease and inflammation. Future studies are warranted that focus on establishing correlations between e-cig types, generations and e-liquid flavours and immunological and toxicological profiles to broaden our understanding about the effects of vaping.

Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 962-971 ◽  
Author(s):  
Yuzhen Wang ◽  
Taoyong Chen ◽  
Chaofeng Han ◽  
Donghua He ◽  
Haibo Liu ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Rab Gtpase ◽  
Type I ◽  
Tlr4 Signaling ◽  
Proinflammatory Mediators ◽  
Mitogen Activated Protein ◽  
Guanosine Triphosphatase

Abstract Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain–containing adapter, inducing interferon (IFN)-β–dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α, IL-6, nitric oxide, and IFN-β, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor κB, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1–positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation.

Ceramide 1-phosphate induces macrophage chemoattractant protein-1 release: involvement in ceramide 1-phosphate-stimulated cell migration

2013 ◽  
Vol 304 (11) ◽  
pp. E1213-E1226 ◽  
Author(s):  
Lide Arana ◽  
Marta Ordoñez ◽  
Alberto Ouro ◽  
Io-Guané Rivera ◽  
Patricia Gangoiti ◽  
...  
Keyword(s):  
Cell Migration ◽  
Inflammatory Responses ◽  
Neutralizing Antibody ◽  
Cell Types ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Monocyte Chemoattractant Protein 1 ◽  
Mitogen Activated Protein ◽  
Ceramide 1 ◽  
Stimulation Of

The bioactive sphingolipid ceramide 1-phosphate (C1P) is implicated in inflammatory responses and was recently shown to promote cell migration. However, the mechanisms involved in these actions are poorly described. Using J774A.1 macrophages, we have now discovered a new biological activity of C1P: stimulation of monocyte chemoattractant protein-1 (MCP-1) release. This novel effect of C1P was pertussis toxin (PTX) sensitive, suggesting the intervention of Giprotein-coupled receptors. Treatment of the macrophages with C1P caused activation of the phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase kinase (MEK)/extracellularly regulated kinases (ERK), and p38 pathways. Inhibition of these kinases using selective inhibitors or specific siRNA blocked the stimulation of MCP-1 release by C1P. C1P stimulated nuclear factor-κB activity, and blockade of this transcription factor also resulted in complete inhibition of MCP-1 release. Also, C1P stimulated MCP-1 release and cell migration in human THP-1 monocytes and 3T3-L1 preadipocytes. A key observation was that sequestration of MCP-1 with a neutralizing antibody or treatment with MCP-1 siRNA abolished C1P-stimulated cell migration. Also, inhibition of the pathways involved in C1P-stimulated MCP-1 release completely blocked the stimulation of cell migration by C1P. It can be concluded that C1P promotes MCP-1 release in different cell types and that this chemokine is a major mediator of C1P-stimulated cell migration. The PI3K/Akt, MEK/ERK, and p38 pathways are important downstream effectors in this action.

scholarly journals Negative Regulation of Interleukin-2 and p38 Mitogen-Activated Protein Kinase during T-Cell Activation by the Adaptor ALX

2006 ◽  
Vol 26 (16) ◽  
pp. 6005-6015 ◽  
Author(s):  
Claire E. Perchonock ◽  
Melissa C. Fernando ◽  
William J. Quinn ◽  
Chau T. Nguyen ◽  
Jing Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Deficient Mice

ABSTRACT Activation of naïve T cells requires synergistic signals produced by the T-cell receptor (TCR) and by CD28. We previously identified the novel adaptor ALX, which, upon overexpression in Jurkat T cells, inhibited activation of the interleukin-2 (IL-2) promoter by TCR/CD28, suggesting that it is a negative regulator of T-cell activation. To further understand the physiological role of ALX, ALX-deficient mice were generated. Purified T cells from ALX-deficient mice demonstrated increased IL-2 production, CD25 expression, and proliferation in response to TCR/CD28 stimulation. Enhanced IL-2 production and proliferation were also observed when ALX-deficient mice were primed in vivo with ovalbumin-complete Freund's adjuvant and then restimulated ex vivo. Consistent with our initial overexpression studies, these data demonstrate that ALX is a negative regulator of T-cell activation. While TCR/CD28-mediated activations of phosphotyrosine induction, extracellular signal-regulated kinase 1/2, Jun N-terminal protein kinase, IκB kinase α/β, and Akt were unaltered, constitutive activation of p38 mitogen-activated protein kinase and its upstream regulators MKK3/6 were observed for ALX-deficient splenocytes. The phenotype of ALX-deficient mice resembled the phenotype of those deficient in the transmembrane adaptor LAX, and an association between ALX and LAX proteins was demonstrated. These results suggest that ALX, in association with LAX, negatively regulates T-cell activation through inhibition of p38.

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