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Proinflammatory Gene Expression (proinflammatory + gene_expression)
Selected AbstractsEffect of intravenous lidocaine administration on laminar inflammation in the black walnut extract model of laminitisEQUINE VETERINARY JOURNAL, Issue 3 2010J. M. WILLIAMS Summary Reasons for performing study: Laminitis is a serious complication of horses suffering from sepsis/endotoxaemia-related events. Laminitis in horses and organ injury in human sepsis are both reported to involve inflammatory injury to the laminae/organs including early activation of endothelium and leucocytes leading to emigration of neutrophils into the tissue interstitium. In the black walnut extract (BWE) model, systemic inflammatory events coincide with marked increase in laminar mRNA concentrations of inflammatory genes including proinflammatory cytokines (i.e. IL-1,, IL-6), COX-2, chemokines (i.e. IL-8) and endothelial adhesion molecules (i.e. ICAM-1 and E-selectin). In models of human sepsis, i.v. lidocaine has been reported to decrease leucocyte and endothelial activation, and the expression of proinflammatory cytokines and chemokines. Objectives: To evaluate the effect of i.v. lidocaine therapy on the inflammatory processes documented to occur in the BWE model of laminitis. Methods: Twelve horses were administered BWE and treated immediately with either lidocaine (1.3 mg/kg bwt bolus, followed by 0.05 mg/kg bwt/min CRI, n = 6) or saline (n = 6) for 10 h. At 10 h post BWE administration, laminar samples were obtained under general anaesthesia for assessment of proinflammatory gene expression (using RT-qPCR) and leucocyte emigration (via CD13 immunohistochemistry). At 0, 3 and 10 h post BWE administration, skin samples were obtained for assessment of leucocyte emigration (via calprotectin immunohistochemistry). Results: No significant differences between groups were noted for inflammatory gene mRNA concentrations (IL-1,, IL-6, IL-8, COX-2) or for number of leucocytes present within the laminar interstitium or skin dermis. Increased (P<0.05) laminar E-selectin mRNA concentrations were present in the LD group (vs. SAL group). Conclusions: Continuous administration of i.v. lidocaine does not inhibit inflammatory events in either the laminae or skin in the horse administered black walnut extract. Potential relevance: This work questions the use of continuous i.v. administration of lidocaine as an effective anti-inflammatory therapy for systemic inflammation. [source] Catalposide, a compound isolated from Catalpa Ovata, attenuates induction of intestinal epithelial proinflammatory gene expression and reduces the severity of trinitrobenzene sulfonic acid-induced colitis in miceINFLAMMATORY BOWEL DISEASES, Issue 5 2004Sang-Wook Kim MD Abstract Certain irinoid-producing plants have been used as herbal anti-inflammatory remedies. Here we evaluated whether catalposide (CATP), a single compound isolated from irinoid-producing plant Catalpa ovata, has a potential for preventing or ameliorating diseases characterized by mucosal inflammation. Preliminary microarray-based gene expression test revealed that CATP, which alone did not significantly affect expression of any of the >8,000 genes analyzed, attenuated the expression of tumor necrosis factor-, (TNF-,)-induced proinflammatory genes including interleukin-8 (IL-8) in human intestinal epithelial HT-29 cells. Down-regulation of IL-8 mRNA accumulation was also reflected by the decreased IL-8 secretion in CATP-treated HT-29 cells. The signal transduction study revealed that CATP significantly attenuates TNF-,-mediated p38 and extracellular signal-regulated kinase (ERK) phosphorylation. Further, CATP reduced NF-,B-mediated transcriptional activation as well as I,-B, degradation. To establish the in vivo relevance of these findings, we examined whether CATP could affect intestinal inflammation in vivo using the mouse model of trinitrobenzene sulfonic acid (TNBS)-induced inflammatory colitis. Intrarectal administration of CATP dramatically reduced the weight loss, colonic damage, and mucosal ulceration that characterize TNBS colitis. Moreover, CATP suppressed the expression of TNF-,, interleukin-1,, and intercellular adhesion molecule-1 along with the inhibition of NF-, B p65 translocation into nucleus in TNBS colitis. Collectively, current results demonstrate that CATP may be an effective agent for the treatment of diseases characterized by mucosal inflammation. [source] NF- ,B in liver diseases: a target for drug therapyJOURNAL OF APPLIED TOXICOLOGY, Issue 2 2009Pablo Muriel Abstract There are five nuclear factor- ,B (NF- ,B) transcription factors with important roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. Several inhibitors of NF- ,B, like caffeic acid, captopril, curcumin, pyrrolidine dithiocarbamate, resveratrol, silymarin and thalidomide, have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the liver. A link between inflammation and hepatocellular carcinoma through the NF- ,B pathway has been observed, providing ample experimental support for the tumor-promoting function of NF- ,B in various models of cancer. NF- ,B has been associated with the induction of proinflammatory gene expression and has attracted interest as a target for the treatment of inflammatory disease. However, despite much attention being focused on the deleterious effects of NF- ,B, activation of this factor during the resolution of inflammation is associated with the production of antiinflammatory molecules like interleukin (IL)-10 and the onset of apoptosis. This suggests that NF- ,B has an antiinflammatory role in vivo involving the regulation of the resolution of inflammation. Also, NF- ,B promotes liver regeneration by upregulating IL-6 and other molecules like hepatocyte growth factor. It has been postulated that the beneficial properties of NF- ,B are due to p50 homodimers, whose activation prevents cholestatic and chronic liver injury. More basic understanding on the function of the diverse NF- ,B factors is urgently needed in different physiological and pathological conditions, because depending on the subunit composition of the dimmer, the disease and the stage of the illness, inhibition of the factor may result in a beneficial or in a deleterious response. Copyright © 2008 John Wiley & Sons, Ltd. [source] Induction of Innate Immune Gene Expression Cascades in Brain Slice Cultures by Ethanol: Key Role of NF-,B and Proinflammatory CytokinesALCOHOLISM, Issue 5 2010Jian Zou Background:, Postmortem human alcoholic brain has increased expression of proinflammatory cytokines (He and Crews, 2007). Nuclear factor ,B (NF-,B) is a transcription factor known to induce proinflammatory cytokine expression. Ethanol exposure increases NF-,B,DNA binding in rat brain (Crews et al., 2006) and in brain slice cultures in vitro (Zou and Crews, 2006). Using hippocampal-entorhinal cortex (HEC) brain slice cultures, we explored the effect of ethanol on NF-,B,DNA binding, proinflammatory gene expression, and sensitivity to glutamate neurotoxicity. Methods:, The HEC brain slice cultures are prepared from rats on P7 and used after 2 weeks in culture. NF-,B,DNA binding is determined by EMSA, NF-,B subunit,DNA binding by ELISA and mRNA by RT-PCR. Multiple antibody immunohistochemistry and confocal microscopy are used to characterize cell types expressing ethanol-induced genes. Results:, Ethanol treatment results in a progressive increase in NF-,B,DNA binding that includes large increases in NF-,B subunit p50 protein,DNA binding. The expression of NF-,B proinflammatory target genes progressively increased with time of ethanol treatment. Ethanol induces proinflammatory cytokines TNF,, MCP-1, and IL-1,, proinflammatory proteases TACE, and tissue plasminogen activator (tPA) as well as inducible nitric oxide synthase. Blockade of NF-,B by using NF-,B p65 siRNA and BHT reduces ethanol induction of proinflammatory genes. Neutralizing antibody to proinflammatory cytokine TNF, reduces ethanol induction of proinflammatory genes, suggesting cytokine propagation of proinflammatory gene induction. Furthermore, neutralizing antibodies to proinflammatory cytokines and protease tPA inhibitors blunt ethanol sensitization to glutamate neurotoxicity. Conclusions:, These findings indicate that ethanol treatment increases NF-,B,DNA binding and proinflammatory gene expression in brain slices. Ethanol-induced innate immune proinflammatory gene induction alters neurotransmission and likely contributes to alcoholic neurodegeneration. [source] Signaling pathways in osteoblast proinflammatory responses to infection by Porphyromonas gingivalisMOLECULAR ORAL MICROBIOLOGY, Issue 2 2008T. Ohno Introduction:, We recently investigated global gene expression in ST2 mouse stromal cells infected by the periodontal pathogen Porphyromonas gingivalis using microarray technology, and found that the bacterium induces a wide range of proinflammatory gene expression. Here, we reported the signaling pathways involved in those proinflammatory responses. Methods:, ST2 cells and primary calvarial osteoblasts from C3H/HeN, C57BL/6, and MyD88-deficient (MyD88,/,) mice were infected with P. gingivalis ATCC33277 and its gingipain-deficient mutant KDP136. Expression of the chemokines CCL5 and CXCL10, and matrix metalloproteinase-9 (MMP9) were quantified by real-time polymerase chain reaction, while phosphorylation of protein kinases and degradation of an inhibitor of nuclear factor-,B, I,B-,, were detected by Western blotting, and activation of transcriptional factors was determined by a luciferase reporter assay. The effects of inhibitors of transcriptional factors and protein kinases were also investigated. Results:, Infection by P. gingivalis elicited gene expression of CCL5, CXCL10, and MMP9 in both ST2 cells and osteoblasts. Western blot and reporter assay results revealed activation of nuclear factor-,B (NF-,B) and activator protein-1 transcription factors. The NF-,B inhibitor suppressed the expression of CCL5 and MMP9, but not that of CXCL10, whereas P. gingivalis infection induced significant CCL5 expression in MyD88,/, osteoblasts. In addition, activation of protease-activated receptors by trypsin elicited significant induction of CXCL10. Conclusion:, Our results suggest that various proinflammatory responses in P. gingivalis -infected stromal/osteoblast cells are NF-,B-dependent, but not always dependent on the Toll-like receptor/MyD88 pathway, while some responses are related to the activation of protease-activated receptors. Thus, P. gingivalis does not fully utilize well-established pathogen recognition molecules such as Toll-like receptors. [source] Altered inflammatory responses in preterm children with cerebral palsyANNALS OF NEUROLOGY, Issue 2 2010Chang-Yi Lin BS Objective Perinatal inflammatory responses contribute to periventricular leukomalacia (PVL) and cerebral palsy (CP) in preterm infants. Here, we examined whether preterm children with CP had altered inflammatory responses when school-aged. Methods Thirty-two preterm children with PVL-induced CP (mean [±standard deviation] age, 7.2 ± 3.6 years) and 32 control preterm children with normal neurodevelopment (6.2 ± 2.2 years) and matched for gestational age were recruited. We measured tumor necrosis factor (TNF)-, levels in the plasma and the supernatants of peripheral blood mononuclear cells (PBMCs) before and after lipopolysaccharide (LPS) stimulation, and proinflammatory gene expression in the PBMCs. Results TNF-, expression was significantly higher in the plasma (p < 0.001) and supernatants of LPS-stimulated PBMCs (p = 0.003) in the CP group than in the control group. After LPS stimulation, the intracellular TNF-, level in the PBMCs was significantly lower in the control group (p = 0.016) and significantly higher in the CP group (p = 0.01). The CP group also had, in their nonstimulated PBMCs, significantly higher mRNA levels of inflammatory molecules: toll-like receptor 4 (TLR-4) (p = 0.0023), TNF-, (p = 0.0016), transforming growth factor-,,activated kinase 1 (p = 0.038), I,B kinase-, (p = 0.029), and c-Jun N-terminal kinase (p = 0.045). The TLR-4 mRNA levels in the PBMCs were highly correlated with TNF-, levels in LPS-stimulated PBMCs (Spearman rank correlation = 0.38, p = 0.03). Interpretation The finding that preterm children with PVL-induced CP have altered inflammatory responses indicates the possibility of programming effect of PVL or inflammation-related events during early life. ANN NEUROL 2010;68:204,212 [source] Suppression of lipopolysaccharide- and tumour necrosis factor-,-induced interleukin (IL)-8 expression by glucocorticoids involves changes in IL-8 promoter acetylationCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2007L. G. Tsaprouni Summary There is accumulating evidence that the transrepressional effect of glucocorticoids in down-regulating proinflammatory gene expression might be regulated by an action on histone acetylation. To investigate this, we studied the effect of two glucocorticoids (dexamethasone and triamcinolone acetonide) on reducing lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-,-induced interleukin (IL)-8 release in a monocytic cell line and two lymphocytic cell lines (HUT-78 and Jurkat). The effect of the histone deacetylase inhibitor trichostatin A (TSA) on LPS- and TNF-,-induced IL-8 release and its repression by glucocorticoids was also examined. LPS and TNF-, induced IL-8 release in all three cell lines and this induction was inhibited by both dexamethasone and triamcinolone. Pretreatment of cells with TSA enhanced basal and LPS- and TNF,-stimulated IL-8 release in all three cell lines. TSA also attenuated the inhibitory effect of glucocorticoids on stimulated IL-8 release. Chromatin immunoprecipitation assays confirmed that LPS and TNF-, enhanced histone acetylation at the IL-8 promoter and that this was inhibited by triamcinolone in all three cell types. Changes in histone acetylation at the IL-8 are important in its regulation by proinflammatory and anti-inflammatory agents, and modulation of this activity may have therapeutic potential in inflammatory conditions. [source] | ||||||||||