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ESE-1 is a novel transcriptional mediator of inflammation that interacts with NF-κB to regulate the inducible nitric-oxide synthase gene

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JOURNAL OF BIOLOGICAL CHEMISTRY 2001年第5期276卷 3302-3309页

作者： Rudders, S Gaspar, J Madore, R Voland, C Grall, F Patel, A Pellacani, A Perrella, MK Libermann, TA Oettgen, P Harvard Univ Sch Med Inst Med Boston MA 02115 USA Beth Israel Deaconess Med Ctr New England Baptist Bone & Joint Inst Boston MA 02115 USA Beth Israel Deaconess Med Ctr Div Cardiol Boston MA 02115 USA Brigham & Womens Hosp Dept Med Boston MA 02115 USA

Inflammation is a hallmark of several vascular diseases. The nuclear factor kappaB (NF-kappaB) transcription factors are dimeric proteins involved in the activation of a large number of genes in response to inflammatory stimuli. We report the involvement of a novel member of the ETS transcription factor, ESE-1, in mediating vascular inflammation. ESE-1 is induced in response to inflammatory cytokines and lipopolysaccharide in vascular smooth muscle cells, endothelial cells, and cells of the monocyte-macrophage lineage. This induction occurs within hours of stimulation and is mediated by NF-kappaB transactivation of the ESE-1 promoter. We have identified the inducible form of nitric-oxide synthase (NOS2) as a putative target for ESE-1, ESE-1 can bind to the p50 subunit of NF-kappaB, and cotransfection of ESE-1 with the p50 and p65 subunits of NF-kappaB synergistically enhances transactivation of the NOS2 promoter by ESE-1, An ESE-1-binding site within the NOS2 promoter has been identified, the site-directed mutagenesis of which completely abolishes the ability of ESE-1 to transactivate the NOS2 promoter. Finally, in a mouse model of endotoxemia, associated with acute vascular inflammation, ESE-1 is strongly expressed in vascular endothelium and smooth muscle cells. In summary, ESE-1 represents a novel mediator of vascular inflammation.

关键词：结合部位钙结合蛋白质类细胞培养的细胞因子类/药理学 DNA结合蛋白质类炎症/代谢炎症介导素类/代谢炎症介导素类/生理学膜糖蛋白类/代谢突变 NF-κB/代谢 NF-κB/生理学神经组织蛋白质类/代谢一氧化氮合酶/代谢一氧化氮合酶Ⅱ型蛋白质结构三级原癌基因蛋白质类突触结合蛋白质Ⅰ 突触结合蛋白质类反式激活因子类/遗传学反式激活因子类/代谢反式激活因子类/生理学转录因子血管疾病/代谢人类

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Eosinophil peroxidase nitrates protein tyrosyl residues - Implications for oxidative damage by nitrating intermediates in eosinophilic inflammatory disorders

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第36期274卷 25933-25944页

作者： Wu, WJ Chen, YH Hazen, SL Cleveland Clin Fdn Lerner Res Inst Dept Cell Biol Cleveland OH 44195 USA Cleveland Clin Fdn Dept Cardiol Cleveland OH 44195 USA Cleveland State Univ Dept Chem Cleveland OH USA

Eosinophil peroxidase (EPO) has been implicated in promoting oxidative tissue injury in conditions ranging from asthma and other allergic inflammatory disorders to cancer and parasitic/helminthic infections. Studies thus far on this unique peroxidase have primarily focused on its unusual substrate preference for bromide (Br-) and the pseudohalide thiocyanate (SCN-) forming potent hypohalous acids as cytotoxic oxidants, However, the ability of EPO to generate reactive nitrogen species has not yet been reported. We now demonstrate that EPO readily uses nitrite (NO2-), a major end-product of nitric oxide ((NO)-N-.) metabolism, as substrate to generate a reactive intermediate that nitrates protein tyrosyl residues in high yield. EPO-catalyzed nitration of tyrosine occurred more readily than bromination at neutral pH, plasma levels of halides, and pathophysiologically relevant concentrations of NO2-. Furthermore, EPO was significantly more effective than MPO at promoting tyrosine nitration in the presence of plasma levels of halides, Whereas recent studies suggest that MPO can also promote protein nitration through indirect oxidation of NO2- with HOCl, we found no evidence that EPO can indirectly mediate protein nitration by a similar reaction between HOBr and NO2-. EPO-dependent nitration of tyrosine was modulated over a physiologically relevant range of SCN- concentrations and was accompanied by formation of tyrosyl radical addition products (e.g. o,o'-dityrosine, pulcherosine, trityrosine), The potential role of specific antioxidants and nucleophilic scavengers on yields of tyrosine nitration and bromination by EPO are examined. Thus, EPO may contribute to nitrotyrosine formation in inflammatory conditions characterized by recruitment and activation of eosinophils.

关键词：嗜酸细胞过氧化物酶嗜酸细胞/酶学炎症/代谢动力学一氧化氮/代谢亚硝酸盐类/代谢氧化性应激过氧化物酶类/代谢酪氨酸/类似物和衍生物酪氨酸/代谢动物

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Mechanisms of prostaglandin E₂ release by intact cells expressing cyclooxygenase-2:: Evidence for a 'Two component' model

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期288卷 1101-1106页

作者： Saunders, MA Belvisi, MG Cirino, G Barnes, PJ Warner, TD Mitchell, JA Univ London Imperial Coll Sci Technol & Med Royal Brompton Hosp Sch Med Natl Heart & Lung InstUnit Crit Care Med London SW3 6NP England

Prostaglandin (PG) release in cells expressing constitutive cyclooxygenase-1 is known to be regulated by liberation of arachidonic acid by phospholipase A(2) followed by metabolism by cyclooxygenase. However, the relative contribution of phospholipase A(2) to the release of PGs in cells expressing cyclooxygenase-2 is not clear. We addressed this question by using radioimmunoassay to measure PGE(2) release by human cells (A549) induced to express cyclooxygenase-2 (measured by Western blot analysis) by interleukin-1 beta. Cells were either unstimulated or stimulated with agents known to activate phospholipase A(2) (bradykinin, Des-Arg(10)-kallidin, or the calcium ionophore A23187) or treated with exogenous arachidonic acid. When cells were treated to express cyclooxygenase-2, the levels of PGE(2) released over 15 min were undetectable;however, in the same cells stimulated with bradykinin, A23187, or arachidonic acid, large amounts of prostanoid were produced. Using selective inhibitors/antagonists, we found that the effects of bradykinin were mediated by B-2 receptor activation and that prostanoid release was due to cyclooxygenase-2, and not cyclooxygenase-1, activity. In addition, we show that the release of PGE(2) stimulated by either bradykinin, A23187, or arachidonic acid was inhibited by the phospholipase A(2) inhibitor arachidonate trifluoromethyl ketone. Hence, we have demonstrated that PGE(2) is released by two components: induction of cyclooxygenase-2 and supply of substrate, probably via activation of phospholipase A(2). This is illustrated in A549 cells by a clear synergy between the cytokine interleukin-1 beta and the kinin bradykinin.

关键词：肾上腺素能β激动剂/药理学肾上腺素能β受体拮抗剂/药理学花生四烯酸/药理学缓激肽/类似物和衍生物缓激肽/药理学卡西霉素/药理学细胞系环氧化酶2 环氧化酶2抑制剂环加氧酶抑制药/药理学地诺前列酮/代谢炎症/代谢白细胞介素1/药理学同工酶类/生物合成胰激肽/类似物和衍生物胰激肽/药理学膜蛋白质类磷脂酶A/生物合成磷脂酶A2 前列腺素内过氧化物合酶类/生物合成受体缓激肽/药物作用人类

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Heparan sulfate proteoglycan isoforms of the CD44 hyaluronan receptor induced in human inflammatory macrophages can function as paracrine regulators of fibroblast growth factor action

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第11期275卷 7964-7974页

作者： Jones, M Tussey, L Athanasou, N Jackson, DG Univ Oxford Nuffield Dept Med MRC Human Immunol UnitInst Mol Med Oxford OX3 9DU England John Radcliffe Hosp Dept Cellular Sci Oxford OX3 9DU England Nuffield Orthopaed Ctr Oxford OX3 7LD England

The CD44 glycoprotein is expressed in multiple isoforms on a variety of cell types where it functions as a receptor for hyaluronan-mediated motility. Recently, interest has centered on CD44 heparan sulfate proteoglycan (HSPG) isoforms because of their potential to sequester heparin-binding growth factors and chemokines. Expression of these isoforms on ectodermal cells has recently been shown to regulate limb morphogenesis via presentation of fibroblast growth factor (FGF) 4/FGF 8 while expression on tumor cells was shown to sequester hepatocyte growth factor and promote tumor dissemination. To date, however, CD44 HSPG expression in tissue macrophages and lymphocytes has not been adequately investigated, despite the fact these cells actively synthesize growth factors and chemokines and indirect evidence that monocyte CD44 sequesters macrophage inflammatory-protein-Ip. Here we show primary human monocytes rather than lymphocytes express CD44 HSPGs, but only following in vitro differentiation to macrophages or activation with the proin-flammatory cytokine interleukin-1 alpha or bacterial lipopolysaccharide. Furthermore, we show these isoforms are preferentially modified with heparan rather than chondroitin sulfate, bind the macrophage-derived growth factors FGF-2, vascular endothelial growth factor, and heparin-binding epidermal growth factor with varying affinities (K-d 25-330 nM) and in the case of FGF-2, can stimulate productive binding to the high affinity tyrosine kinase FGF receptor 1 (FGFR1). In contrast, we find no evidence for significant binding to C-C chemokines. Last, we confirm by immunofluorescent antibody staining that inflamed synovial membrane macrophages express CD44 HSPGs and that expression is greatest in cells containing high FGF-2 levels. These results suggest a paracrine role for macrophage CD44 HSPG isoforms in the regulation of growth factor action during inflammation.

关键词：细胞分化炎症趋化因子类/代谢内皮生长因子/代谢表皮生长因子/代谢成纤维细胞生长因子2/代谢类肝素硫酸蛋白聚糖类/代谢炎症/代谢炎症介导素类/代谢胞间信号肽类和蛋白质类白细胞介素1/代谢淋巴因子/代谢巨噬细胞/细胞学巨噬细胞/免疫学单核细胞/细胞学单核细胞/免疫学旁分泌细胞细胞间通讯蛋白质结合蛋白质亚型/代谢受体蛋白质酪氨酸激酶类/代谢受体成纤维细胞生长因子 1型受体成纤维细胞生长因子/代谢滑膜/免疫学滑膜/病理学血管内皮生长因子A 血管内皮生长因子类人类

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Aldosterone-induced inflammation in the rat heart - Role of oxidative stress

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AMERICAN JOURNAL OF PATHOLOGY 2002年第5期161卷 1773-1781页

作者： Sun, Y Zhang, JK Lu, L Chen, SS Quinn, MT Weber, KT Univ Tennessee Ctr Hlth Sci Div Cardiovasc Dis Dept Med Memphis TN 38163 USA Montana State Univ Dept Vet Mol Biol Bozeman MT 59717 USA

Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 mug/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daffy) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure;immunohistochemical detection of NADPH oxidase expression and activity, analysis of redox-sensitive nuclear factor-kappaB activation;in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-a mRNA expression;monitoring cell growth and infiltration of macrophages and T cells;and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart However, at weeks 4 and 5 of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in tim

关键词：醛固酮/药理学抗氧化剂/药理学心肌疾病/化学诱导心肌疾病/免疫学心肌疾病/代谢细胞分裂细胞运动纤维化心脏/药物作用免疫因子类/生物合成免疫因子类/遗传学炎症/化学诱导炎症/免疫学炎症/代谢淋巴细胞/免疫学巨噬细胞/免疫学单核细胞/免疫学心肌/免疫学心肌/代谢心肌/病理学 NADPH氧化酶/代谢 NF-κB/代谢氧化性应激 RNA 信使/生物合成大鼠 Sprague-Dawley 螺内酯/药理学酪氨酸/类似物和衍生物酪氨酸/分析动物男(雄)性大鼠

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Protease-activated receptors: sentries for inflammation?

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TRENDS IN PHARMACOLOGICAL SCIENCES 2000年第3期21卷 103-108页

作者： Cocks, TM Moffatt, JD Royal Melbourne Hosp Dept Cardiac Surg Parkville Vic 3051 Australia Univ Melbourne Dept Pharmacol Parkville Vic 3010 Australia

Cell-surface protease-activated receptors (PARs) appear to have evolved to detect extracellular enzymatically active serine proteases such as trypsin and thrombin. The predominant location of PARs on endothelia and epithelia and the discovery of enzymes such as trypsin within these tissues, together with the linkage of PARs to cytoprotective pathways, provide new information on autocrine and paracrine signalling within these critical barriers. In this article, the ways in which the distribution and function of PARs could be harnessed by pharmacologists as novel anti-inflammatory therapeutic strategies are discussed.

关键词：酶激动剂类炎症/酶学炎症/代谢炎症/病理学受体 PAR-1 受体细胞表面/代谢受体细胞表面/生理学受体凝血酶/代谢受体凝血酶/生理学动物人类

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Induction of β-family chemokines mRNA in human embryonic astrocytes by inflammatory cytokines and measles virus protein

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JOURNAL OF NEUROCYTOLOGY 1998年第8期27卷 575-580页

作者： Xiao, BG Mousa, A Kivisäkk, P Seiger, Å Bakhiet, M Link, H Karolinska Inst Huddinge Univ Hosp Div Neurol Stockholm Sweden Karolinska Inst Huddinge Univ Hosp Dept Clin Neurosci & Family Med Div Geriatr Med Stockholm Sweden

The cellular infiltration found during CNS inflammation consists of monocytes and activated T cells, suggesting the presence of cell-specific chemotactic signals during inflammatory responses. Astrocyte chemokine expression might contribute to site-specific leukocyte infiltration within the CNS. To investigate the factors that regulate astrocyte chemokine expression, we examined the ability of human fetal astrocytes to induce beta-family chemokine mRNA. Astrocyte-derived monocyte chemoattractant protein-1 (MCP-1), RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta mRNA were easily induced by lipopolysaccharide and/or the proinflammatory cytokines (IFN gamma and/or TNF-alpha), respectively. Addition of both IFN gamma and TNF-alpha together did not lead to an additive effect but resulted in the inhibition of MCP-1 and MIP-1 beta mRNA expression, indicating that interaction between chemokines and cytokines may play a key role in regulating the local immune response of resident and infiltrating cells at the site of lesion. Interestingly, ultraviolet light-inactivated measles virus, but not cytomegalovirus, strongly induced expression of MCP-1, RANTES, MIP-1 alpha, and MIP-1 beta mRNA in human embryonic astrocytes, especially MCP-1 and MIP-1 beta. An association occurs between the beta-family chemokine expression in astrocytes and inflammatory factors/virus, suggesting a possible role for beta-family chemokines in the pathogenesis of CNS inflammatory disease.

关键词：星形细胞/药物作用星形细胞/代谢细胞培养的趋化因子 CC/生物合成细胞因子类/药理学巨细胞病毒/免疫学剂量效应关系药物神经胶质原纤维酸性蛋白质/代谢免疫组织化学炎症/代谢干扰素Ⅱ型/药理学脂多糖类/药理学麻疹病毒/免疫学 RNA 信使/生物合成肿瘤坏死因子α/药理学病毒蛋白质类/药理学人类

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When engineered to produce latent TGF-β1, antigen specific T cells down regulate Th1 cell-mediated autoimmune and Th2 cell-mediated allergic inflammatory processes

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CYTOKINE & GROWTH FACTOR REVIEWS 2000年第1-2期11卷 89-96页

作者： Thorbecke, GJ Umetsu, DT deKruyff, RH Hansen, C Chen, LZ Hochwald, GM NYU Sch Med Dept Pathol New York NY 10016 USA Stanford Univ Dept Pediat Div Immunol & Transplantat Biol Stanford CA 94305 USA NYU Sch Med Dept Neurol New York NY 10016 USA

To determine whether T cells which produce large amounts of latent TGF-beta 1 are capable of down-regulating autoimmune and allergic disease, myelin basic protein (MBP)-specific and ovalbumin (OVA)-specific BALB/c cloned Th1 cells were transduced with cDNA for murine TGF-beta 1 by coculture with fibroblasts producing a genetically engineered retrovirus. The transduced MBP-specific Th1 cells were found to lose the capacity to provoke EAE in BALB/c mice, and to gain instead the ability to protect against E4E in (SJL x BALB/c) Fl mice immunized with proteolipid protein (PLP). This protective effect was not obtained with OVA-specific TGF-beta 1 transduced Th1 cells. The transduced OVA-specific Thl cells did protect against airway hyperreactivity induced by Th2-cell mediated responses to inhaled OVA. This effect was again antigen specific and could not be obtained with untransduced OVA-specific Thl cells. In both cases these effects of antigen specific TGF-beta 1 transduced T cells were nullified by administration of neutralizing anti-TGF-beta mAb. Thus, the antigen specificity of the cloned T cells allows the site-specific local delivery of therapeutic active TGF-beta 1 to both Thl and Th2 cell-mediated inflammatory infiltrates, (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：自身免疫疾病/代谢自身免疫/生理学支气管高反应性/遗传学支气管高反应性/免疫学支气管高反应性/代谢疾病模型动物超敏反应/免疫学超敏反应/代谢炎症/免疫学炎症/代谢髓磷脂碱性蛋白质类/遗传学髓磷脂碱性蛋白质类/代谢 T淋巴细胞/生理学 Th1细胞/免疫学 Th2细胞/免疫学转化生长因子β/代谢动物小鼠

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Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 303-312页

作者： Mascia, F Mariani, V Girolomoni, G Pastore, S Ist Dermopat Immacolata Ist Ricovero & Cura Carottere Sci Immunol Lab I-00167 Rome Italy

During inflammatory skin disorders such as psoriasis, atopic dermatitis, and allergic contact dermatitis, epidermal keratinocytes overexpress large amounts of soluble epidermal growth factor receptor ligands in response to tumor necrosis factor a and interferon gamma. These cytokines also promote de novo synthesis of numerous chemokines, including CCL2/MCP-1, CCL5/RANTES, CXCL10/EP-10, and CXCL8/IL-8, in turn responsible for the recruitment of different leukocyte populations. This study demonstrates that stimulation of EGFR down-regulates CCL2, CCL5, and CXCL10, while it increases CXCL8 expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, and reduced CXCL8 expression. In a mouse model of contact hypersensitivity, a single topical administration of a selective EGFR kinase blocker before antigen challenge results in a markedly enhanced immune response with increased chemokine expression and heavier inflammatory cell infiltrate. Targeting EGFR on epithelial cells may thus have profound impact on inflammatory and immune responses.

关键词：细胞培养的炎症趋化因子类/遗传学炎症趋化因子类/免疫学炎症趋化因子类/代谢培养技术皮炎接触性/免疫学皮炎接触性/代谢疾病模型动物炎症/免疫学炎症/代谢干扰素γ/代谢角蛋白细胞/细胞学角蛋白细胞/免疫学角蛋白细胞/代谢小鼠近交BALBC 信号传导/生理学皮肤/细胞学皮肤/免疫学皮肤/代谢皮肤/病理生理学转录激活转化生长因子α/遗传学转化生长因子α/代谢肿瘤坏死因子α/代谢成年人动物女(雌)性人类男(雄)性小鼠

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The Rel/NF-κB family:: friend and foe

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TRENDS IN BIOCHEMICAL SCIENCES 2000年第9期25卷 434-440页

作者： Perkins, ND Univ Dundee Dept Biochem Div Gene Regulat & Express Dundee DD1 5EH Scotland

The members of the Rel/NF-kappa B family of transcription factors form one of the first lines of defense against infectious diseases and cellular stress. These proteins initiate a highly coordinated response in multiple cell types that effectively counteracts the threat to the health of the organism, Conversely, disruption of the regulatory mechanisms that control the specificity and extent of this response, which results in aberrant activation of NF-kappa B, can be one of the primary causes of a wide range of human diseases. Thus, targeting NF-kappa B might lead to the development of new pharmaceutical reagents that could provide novel treatments for many inflammatory diseases and cancer.

关键词：细胞凋亡细胞分裂细胞系细胞核/代谢 I-κB蛋白质类/化学 I-κB蛋白质类/遗传学 I-κB蛋白质类/生理学炎症/代谢模型生物学多基因族 NF-κB/化学 NF-κB/遗传学 NF-κB/生理学肿瘤转录遗传动物人类

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