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The MAPK kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation

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JOURNAL OF BIOLOGICAL CHEMISTRY 2001年第5期276卷 3508-3516页

作者： Holtmann, H Enninga, J Kälble, S Thiefes, A Dörrie, A Broemer, M Winzen, R Wilhelm, A Ninomiya-Tsuji, J Matsumoto, K Resch, K Kracht, M Hannover Med Sch Inst Pharmacol D-30625 Hannover Germany Nagoya Univ Grad Sch Sci Dept Mol Biol Nagoya Aichi 4648602 Japan

Mechanisms of fulminant gene induction during an inflammatory response were investigated using expression of the chemoattractant cytokine interleukin-8 (IL-8) as a model. Recently we found that coordinate activation ofNF-kappaB and c-Jun N-terminal protein kinase (JNK) is required for strong IL-8 transcription, whereas the p38 MAP kinase (MAPK) pathway stabilizes the IL-8 mRNA It is unclear how these pathways are coupled to the receptor for IL-1, an important physiological inducer of IL-8. Expression of the MAP kinase kinase kinase (MAPKKK) TAK1 together with its coactivator TAB1 in HeLa cells activated all three pathways and was sufficient to induce IL-8 formation, NF-kappaB + JNK2-mediated transcription from a minimal IL-8 promoter, and p38 MAPK-mediated stabilization of a reporter mRNA containing IL-8-derived regulatory mRNA sequences. Expression of a kinase-inactive mutant of TAK1 largely blocked IL-1-induced transcription and mRNA stabilization, as well as formation of endogenous IL-8. Truncated TAB1, lacking the TAK1 binding domain, or a TAK1-derived peptide containing a TAK1 autoinhibitory domain were also efficient in inhibition. These data indicate that the previously described three-pathway model of IL-8 induction is operative in response to a physiological stimulus, IL-1, and that the MAPKKK TAK1 couples the IL-1 receptor to both transcriptional and RNA-targeted mechanisms mediated by the three pathways.

关键词：衔接蛋白质类信号转导载体蛋白质类/遗传学载体蛋白质类/生理学酶激活基因表达调控/生理学珠蛋白类/遗传学珠蛋白类/代谢 HeLa细胞白细胞介素8/生物合成白细胞介素8/遗传学细胞内信号肽和蛋白质类 JNK丝裂原活化蛋白激酶类 MAP激酶激酶4 MAP激酶激酶激酶类/遗传学 MAP激酶激酶激酶类/生理学丝裂原激活蛋白激酶激酶类/代谢丝裂原激活蛋白激酶类/代谢突变 NF-κB/代谢 RNA稳定性 RNA 信使/代谢受体白细胞介素1/生理学受体白细胞介素8A/遗传学受体白细胞介素8A/代谢转录遗传/生理学 p38丝裂原活化蛋白激酶类人类

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Interleukin-10 inhibits elevated chemokine interleukin-8 and regulated on activation normal T cell expressed and secreted production in cystic fibrosis bronchial epithelial cells by targeting the l_kB kinase α/β complex

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期162卷 293-302页

作者： Tabary, O Muselet, C Escotte, S Antonicelli, F Hubert, D Dusser, D Jacquot, J Hop Trousseau Unite Biol Mol INSERM E213 F-75571 Paris France INSERM U514 Reims France CNRS Biochim Lab Reims France Hop Cochin Serv Pneumol F-75674 Paris France

Accumulating evidence suggests that in cystic fibrosis (CF) patients, airway fluids are characterized by decreased antibacterial activity, elevated NaCl concentration, and high levels of chemokines, resulting in exaggerated activation of the transcriptional nuclear factor (NF)-kappaB in airway epithelial cells. The present study was undertaken to evaluate the effects of anti-inflammatory cytokine interleukin-10 (IL-10) on NaCl-induced chemokine IL-8 and regulated on activation normal T cell expressed and secreted (RANTES) expression through the NF-kappaB signaling in primary DeltaF508 CF and non-CF (control) human bronchial epithelial cells. Exposure of CF and non-CF bronchial epithelial cells to hypertonic (170 mmol/L NaCl) milieu compared to isotonic (115 mmol/L NaCl) and hypotonic (85 mmol/L NaCl) milieu caused a significant, NaCl-dependent increase in IL-8 and RANTES gene expression and protein production. Compared to non-CF cells, CF bronchial epithelial cells were characterized by a higher susceptibility to produce elevated IL-8 and RANTES production in an hypertonic NaCl milieu in response to IL-1beta activation. Treatment with IL-10 suppressed IL-8 and RANTES gene expression in both non-CF and CF bronchial epithelial cells was associated with a reduced expression of IkB (IKK) alpha/beta kinases, particularly for IKKalpha which is greater expressed in CF bronchial epithelial cells, and resulting in reduced NF-kappaB activation. These findings suggest that IL-10 might have anti-inflammatory benefits in airways of CF patients.

关键词：支气管/病理学细胞培养的趋化因子CCL5/拮抗剂和抑制剂趋化因子CCL5/生物合成趋化因子CCL5/遗传学炎症趋化因子类/拮抗剂和抑制剂炎症趋化因子类/生物合成炎症趋化因子类/遗传学囊性纤维化/代谢囊性纤维化/病理学上皮细胞/药物作用上皮细胞/代谢上皮细胞/病理学基因表达/药物作用 I-κB激酶 I-κB蛋白质类/代谢白细胞介素1/药理学白细胞介素10/药理学白细胞介素8/拮抗剂和抑制剂白细胞介素8/生物合成白细胞介素8/遗传学大分子物质 NF-κB/代谢蛋白质丝氨酸苏氨酸激酶/代谢呼吸道黏膜/药物作用呼吸道黏膜/代谢呼吸道黏膜/病理学氯化钠/药理学肿瘤坏死因子α/药理学人类

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Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit

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MOLECULAR AND CELLULAR BIOLOGY 1999年第7期19卷 4798-4805页

作者： Sizemore, N Leung, S Stark, GR Cleveland Clin Fdn Lerner Res Inst Dept Mol Biol Cleveland OH 44195 USA Berlex Biosci Dept Immunol Richmond CA 94804 USA

The work of Reddy et al. (S. A. Reddy, J. A. Huang, and W. S. Liao, J. Biol. Chem. 272:29167-29173, 1997) reveals that phosphatidylinositol 3-kinase (PI3K) plays a role in transducing a signal from the occupied interleukin-1 (IL-1) receptor to nuclear factor KB (NF-kappa B), but the underlying mechanism remains to be determined. We have found that IL-1 stimulates interaction of the IL-1 receptor accessory protein with the p85 regulatory subunit of PI3K, leading to the activation of the p110 catalytic subunit. Specific PI3K inhibitors strongly inhibit both PI3K activation and NF-kappa B-dependent gene expression but have no effect on the IL-1-stimulated degradation of I kappa B alpha, the nuclear translocation of NK-kappa B, or the ability of NF-kappa B to bind to DNA. In contrast, PI3K inhibitors block the IL-1-stimulated phosphorylation of NF-kappa B itself, especially the p65/RelA subunit. Furthermore, by using a fusion protein containing the p65/RelA transactivation domain, we found that overexpression of the p110 catalytic subunit of PI3K induces p65/RelA-mediated transactivation and that the specific PI3K inhibitor LY294,002 represses this process. Additionally, the expression of a constitutively activated form of either p110 or the PI3K-activated protein kinase Akt also induces p65/RelA-mediated transactivation. Therefore, IL-1 stimulates the PI3K-dependent phosphorylation and transactivation of NF-kappa B, a process quite distinct from the liberation of NF-kappa B from its cytoplasmic inhibitor I kappa B.

关键词：雄二烯类/药理学结合部位生物转运细胞核/代谢色酮类/药理学细胞质/代谢 DNA/代谢 DNA结合蛋白质类/代谢酶激活酶抑制剂/药理学基因表达调控/药物作用 I-κB蛋白质类白细胞介素1/代谢白细胞介素1/药理学白细胞介素8/遗传学吗啉类/药理学 NF-κB/拮抗剂和抑制剂 NF-κB/代谢磷酸肌醇3-激酶类/拮抗剂和抑制剂磷酸肌醇3-激酶类/代谢磷酰化受体白细胞介素1/代谢信号传导转录因子RelA 肿瘤细胞培养的人类

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Interleukin-8 levels in human lung epithelial cells are increased in response to coal fly ash and vary with the bioavailability of iron, as a function of particle size and source of coal

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CHEMICAL RESEARCH IN TOXICOLOGY 2000年第2期13卷 118-125页

作者： Smith, KR Veranth, JM Hu, AA Lighty, JS Aust, AE Utah State Univ Dept Chem & Biochem Logan UT 84322 USA Univ Utah Dept Chem & Fuels Engn Salt Lake City UT 84112 USA

Particulate air pollution contains iron, and some of the pathological effects after inhalation may be due to radical species produced by iron-catalyzed reactions. We tested the hypothesis that iron present in coal fly ash (CFA) could induce the expression and synthesis of the inflammatory cytokine interleukin-8 (IL-8). CFA, containing as much as 14% iron, was used as a model combustion source particle. Three coal types were used to generate three size fractions enriched in particles [submicron (<1 mu m), fine (<2.5 mu m), or coarse (2.5-10 mu m)], as well as the fraction of >10 mu m. Treatment of human lung epithelial (A549) cells for 4 h with CFA from Utah enriched in <1 mu m particles (20 mu g/cm(2)) resulted in a 2.6-fold increase in mRNA levels for IL-8. IL-8 levels were increased in the medium by as much as 8-fold when cells were treated with the fraction enriched in the smallest size Utah CFA for 24 h. IL-8 production was completely inhibited when the CFA was pretreated with the metal chelator desferrioxamine B, suggesting that a transition metal was responsible for the induction, probably iron. Treatment with a soluble form of iron, ferric ammonium citrate (FAC), mimicked the IL-8 level increase observed with CFA. There was a direct relationship, above a threshold level of bioavailable iron, between the levels of IL-8 and bioavailable iron in A549 cells treated with CFA or FAC. Further, the relationship between IL-8 and bioavailable iron for CFA was indistinguishable from that for FAC. These results strongly suggest that iron can induce IL-8 in A549 cells and that iron was the likely component of CFA that induced IL-8. CFA-induced IL-8 production was inhibited by tetramethylthiourea or dimethyl sulfoxide, suggesting that radical species were involved in the induction. These results demonstrate that iron present in CFA may be responsible for production and release of inflammatory mediators by the lung epithelium through generation of radical species and sugges

关键词：生物利用度碳/药理学细胞系煤去铁胺/药理学上皮细胞/药物作用上皮细胞/代谢正铁化合物/药理学铁蛋白质类/分析白细胞介素8/遗传学白细胞介素8/代谢铁/代谢粒子大小颗粒物肺泡/药物作用肺泡/代谢季胺类化合物/药理学 RNA 信使/代谢人类

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Persistent depletion of I kappa B alpha and interleukin-8 expression in human pulmonary epithelial cells exposed to quartz particles

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TOXICOLOGY AND APPLIED PHARMACOLOGY 2000年第2期167卷 107-117页

作者： Schins, RPF McAlinden, A MacNee, W Jimenez, LA Ross, JA Guy, K Faux, SP Donaldson, K Napier Univ Dept Sci Biol Edinburgh EH14 1DJ Midlothian Scotland Univ Edinburgh Resp Med Unit Colt Labs ELEGI Edinburgh EH8 9YL Midlothian Scotland Univ Edinburgh Dept Surg Edinburgh EH8 9YL Midlothian Scotland Univ Leicester MRC Toxicol Unit Leicester LE1 7RH Leics England

Chronic inflammation and fibrosis following quartz inhalation has been associated with persistent up-regulation of several "proinflammatory" genes, which are commonly regulated by nuclear factor kappa-B (NF-kappa B). Transcription of the NF-kappa B-inhibitor I kappa B alpha is also under NF-kappa B control, and its de novo synthesis is considered to comprise a negative feedback loop in transient inflammation. To investigate this mechanism in particle inflammation, we have studied I kappa B alpha degradation in A549 cells exposed to DQ12-quartz or TiO2, in relation to the expression of IL-8. Although both quartz and TiO2 were found to cause I kappa B alpha degradation, only quartz elicited a mild I kappa B alpha depletion, first appearing at 4 h. TiO2 was found to cause a higher short-term increase in I kappa B alpha mRNA-expression compared to quartz, whereas the early enhancement of IL-8 expression and release was similar for both particles. Up-regulation of IL-8 expression was found to persist with quartz only. Cotreatment with PDTC and curcumin reduced particle-elicited IL-8 response, whereas cycloheximide caused enhancement of IL-8 mRNA expression in both the quartz- and TiO2-treated cells. Our results demonstrate that mineral dusts cause I kappa B alpha degradation, a transient increase in de novo synthesis of I kappa B alpha, and enhanced IL-8 expression in human pulmonary epithelial cells. While I kappa B alpha degradation and early IL-8 expression seem to be general particle phenomena, particle-specific characteristics impact on activation of I kappa B alpha gene transcription, apparently accounting for the different proinflammatory IL-8 responses seen with quartz and TiO2 in the longer term. These observations may provide an explanation for the transient versus the persistent pulmonary inflammatory status and subsequent differences in pathogenic potency of TiO2 and quartz. (C) 2000 Academic Press.

关键词：印迹法蛋白质姜黄素/药理学放线菌酮/药理学 DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢上皮细胞/药物作用上皮细胞/代谢 I-κB蛋白质类白细胞介素8/遗传学白细胞介素8/代谢肺/细胞学肺/药物作用肺/代谢 NF-κB/拮抗剂和抑制剂脯氨酸/类似物和衍生物脯氨酸/药理学石英/毒性 RNA 信使/代谢逆转录聚合酶链反应硫代氨基甲酸酯类/药理学钛/毒性肿瘤细胞培养的增量调节人类

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Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1β, IL-6, IL-8, IL-10 and TNF-α from normal human mononuclear cells involving in the lupus pathogenesis

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IMMUNOLOGY 2000年第3期99卷 352-360页

作者： Sun, KH Yu, CL Tang, SJ Sun, GH Natl Yang Ming Univ Fac Med Technol Taipei 112 Taiwan Natl Yang Ming Univ Inst Biotechnol Med Taipei 112 Taiwan Natl Taiwan Univ Coll Med Dept Med Taipei Taiwan Natl Taiwan Univ Coll Med Inst Mol Med Taipei Taiwan Natl Taiwan Ocean Univ Inst Marine Biotechnol Taipei Taiwan Tri Serv Gen Hosp Dept Surg Div Urol Taipei Taiwan Natl Def Med Ctr Taipei Taiwan

In our previous reports, we found polyclonal anti-double-stranded DNA antibodies (anti-dsDNA) purified from patients with active systemic lupus erythematosus (SLE) exerted inhibitory effect on [H-3]thymidine incorporation of human mononuclear cells (MNC). However, the other immunological effects of anti-dsDNA on the functions of MNC have not yet been reported. In this study, two monoclonal antibodies, 12B3 and 9D7, with different anti-dsDNA activity were evaluated for their effects on the expression and release of different cytokines from human MNC. We confirmed absence of endotoxin in the two monoclonal antibody preparations and the used medium as detected by Limulus amoebocyte lysate test. The mRNA expression and release of different cytokines including interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were measured. We found the two monoclonal anti-dsDNA not only dose-responsively suppressed the phytohaemagglutinin (PHA)-induced thymidine uptake of human MNC but stimulated the mRNA expression of IL-1 beta, IL-6 and IL-8 in normal human MNC detected by reverse transcription-polymerase chain reaction (RT-PCR). Enzyme-linked immunosorbent assay (ELISA) measurement of cytokines in MNC culture supernatants revealed that anti-dsDNA enhanced IL-1 beta, IL-8, TNF-alpha and IL-10 release from resting MNC. These effects of anti-dsDNA antibodies were not affected by polymyxin B, a potent binder and neutralizer of lipopolysaccharide (LPS). These in vitro studies suggest that anti-dsDNA possess a dual effect on normal human MNC: (a) to enhance the release of proinflammatory cytokines (IL-1 beta, IL-8 and TNF-alpha) from MNC to augment inflammatory reaction;and (b) to polarize the immune reaction towards the T helper 2 (Th2) (increased IL-10 production) pathway. This unique effect of anti-dsDNA may play a role in lupus pathogenesis by augmenting inflammatory reactions and autoantibody production wh

关键词：抗体抗核/免疫学抗体抗核/分离和提纯抗体抗核/代谢细胞培养的细胞因子类/分析细胞因子类/生物合成细胞因子类/遗传学酶联免疫吸附测定肾小球膜/细胞学肾小球膜/免疫学白细胞介素1/分析白细胞介素1/生物合成白细胞介素1/遗传学白细胞介素10/分析白细胞介素10/生物合成白细胞介素10/遗传学白细胞介素2/分析白细胞介素2/生物合成白细胞介素2/遗传学白细胞介素4/分析白细胞介素4/生物合成白细胞介素4/遗传学白细胞介素6/分析白细胞介素6/生物合成白细胞介素6/遗传学白细胞介素8/分析白细胞介素8/生物合成白细胞介素8/遗传学 Jurkat细胞白细胞单核/免疫学脂多糖类/药理学红斑狼疮系统性/免疫学蛋白质结合 RNA 信使/分析逆转录聚合酶链反应统计学非参数胸苷/代谢转录遗传肿瘤坏死因子α/分析肿瘤坏死因子α/生物合成肿瘤坏死因子α/遗传学动物人类小鼠大鼠

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The mechanism of taurine chloramine inhibition of cytokine (interleukin-6, interleukin-8) production by rheumatoid arthritis fibroblast-like synoviocytes

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ARTHRITIS AND RHEUMATISM 2000年第10期43卷 2169-2177页

作者： Kontny, E Szczepanska, K Kowalczewski, J Kurowska, M Janicka, I Marcinkiewicz, J Maslinski, W Inst Rheumatol Dept Pathophysiol & Immunol PL-02637 Warsaw Poland Jagiellonian Univ Coll Med Krakow Poland Med Univ Warsaw Warsaw Poland

Objective, Taurine chloramine (Tau-Cl) has been shown to inhibit the production of proinflammatory cytokines (interleukin-6 [IL-6] and IL-8) by fibroblastlike synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients, The present study was conducted to elucidate the mechanism of inhibitory action exerted by Tau-Cl, Methods. The effects of Tau-Cl on 1) the transcription of genes coding for IL-6 and IL-8, and 2) the activity of nuclear factor kappa B (NF-kappa B) and activator protein 1 (AP-1) transcription factors, which are crucial for the transcription of these cytokine genes, were investigated in FLS isolated from the synovial tissue of RA patients. FLS were cultured in vitro for 3-6 passages and stimulated with recombinant human IL-1 beta (1 ng/ mi) in the presence of either Tau or Tau-Cl, which were added simultaneously with the stimulus at concentrations of 250 mu M or 500 mu M. The relative expression of IL-6 and IL-8 messenger RNA (mRNA) was evaluated after 4 hours of stimulation, using competitive reverse transcriptase-polymerase chain reaction. The DNA binding activity of NF-kappa B and AP-1 was examined 30 minutes and 2 hours after cell stimulation, respectively, using electromobility gel shift assay. Results. IL-1 beta triggered a significant rise in the activity of transcription factors NF-kappa B and AP-1, followed by an elevation of cytokine IL-6 and IL-8 mRNA expression. Tau-Cl, but not Tau, reduced IL-1 beta-triggered cytokine mRNA expression, exerting stronger inhibitory activity on the levels of IL-6 than on those of IL-8, Importantly, Tau-Cl also diminished the activity of NF-kappa B and, to a lesser extent, that of AP-1 transcription factor. Neither IL-1 beta nor Tau-Cl affected the activity of octamer transcription factor 1, Conclusion. Tau-Cl inhibition of IL-6 and IL-8 synthesis in FLS from RA patients results from the ability of this compound to diminish the activity of the major transcriptional regulators (NF-kappa B and AP-1), whi

关键词：关节炎类风湿/代谢关节炎类风湿/病理学 DNA结合蛋白质类/药物作用成纤维细胞/细胞学宿主细胞因子C1 炎症介导素类/药理学白细胞介素6/拮抗剂和抑制剂白细胞介素6/生物合成白细胞介素6/遗传学白细胞介素8/拮抗剂和抑制剂白细胞介素8/生物合成白细胞介素8/遗传学 NF-κB/药物作用八聚体转录因子1 滑膜/代谢滑膜/病理学牛磺酸/类似物和衍生物牛磺酸/药理学转录因子AP-1/药物作用转录因子/药物作用转录遗传/药物作用老年人女(雌)性人类男(雄)性中年人

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Human thymocytes express CCR-3 and are activated by eotaxin

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BLOOD 1999年第10期93卷 3233-3240页

作者： Franz-Bacon, K Dairaghi, DJ Boehme, SA Sullivan, SK Schall, TJ Conlon, PJ Taylor, N Bacon, KB Neurocrine Biosci Inc Dept Immunol San Diego CA 92121 USA DNAX Res Inst Mol & Cellular Biol Inc Dept Immunol Palo Alto CA 94304 USA DNAX Res Inst Mol & Cellular Biol Inc Dept Mol Biol Palo Alto CA 94304 USA Inst Genet Mol CNRS UMR 5535 Montpellier France

Eotaxin has been characterized as a chemokine involved in eosinophil activation;however, mRNA for this C-C chemokine has been shown to be constitutively expressed in thymus. Immunohistochemical analysis showed a punctate distribution pattern, with eotaxin expression localized mainly in the medulla and in Hassle's corpuscles. Moreover, the receptor for eotaxin, CCR-3, was detected on thymocytes, with the highest level of expression being on the CD8 single-positive population. Equilibrium binding analyses on unfractionated thymocytes demonstrated specific I-125-eotaxin binding profiles comparable with CCR-3 transfectants. Eotaxin induced cell migration and mobilization of intracellular calcium in all thymocytes except the immature CD4(-)/CD8(-) population. Eotaxin also induced the secretion of the chemokines interleukin-8, RANTES, and macrophage inflammatory protein-1 beta from thymocyte cultures in vitro. These results suggest that eotaxin-induced thymocyte activation may have important physiological implications for lymphocyte mobilization within and from this lymphoid organ. (C) 1999 by The American Society of Hematology.

关键词： CD8阳性T淋巴细胞/免疫学钙/代谢细胞培养的趋化因子 CC 趋化因子嗜酸细胞/免疫学趋化因子嗜酸细胞/药理学趋化性白细胞细胞因子类/遗传学细胞因子类/免疫学细胞因子类/药理学白细胞介素8/生物合成白细胞介素8/遗传学受体趋化因子/生物合成受体趋化因子/遗传学受体 HIV/遗传学逆转录聚合酶链反应 T淋巴细胞亚群/免疫学 T淋巴细胞/药物作用 T淋巴细胞/免疫学胸腺/免疫学人类婴儿婴儿新生

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Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第11期97卷 6043-6048页

作者： Nanthakumar, NN Fusunyan, RD Sanderson, I Walker, WA Harvard Univ Sch Med Massachusetts Gen HospDev Gastroenterol Lab Dept PediatCombined Program Pediat Gastroenterol Charlestown MA 02129 USA Univ London St Bartholomews Hosp Acad Dept Paediat Gastroenterol & Nutr London England

Necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in premature infants, occurs after the introduction of oral feedings in conjunction with initial bacterial colonization of the gut and is hypothesized to be due to an immature (inappropriate) enterocyte response to bacterial stimuli. To test this hypothesis, we compared the enterocyte IL-8 response to inflammatory stimuli [lipopolysaccharide (LPS) and IL-1 beta] in immature vs. mature human small intestine. Initial in vitro studies comparing confluent Caco-2 cells, a model for mature human enterocytes, with a primary human fetal intestinal cell line (H4 cells) demonstrated that after inflammatory stimulation fetal cells secreted more IL-8 (LPS, 8-fold;IL-1 beta, 20-fold) than Caco-2 cells. IL-8 mRNA activity in fetal compared to Caco-2 cells was proportionately increased by the same magnitude with both stimuli. To validate the in vitro observations, small intestinal organ cultures from fetuses vs. older children were exposed to LPS and IL-1 beta. Again in human organ cultures from fetuses compared to older children, IL-8 secretion was greater (LPS, 2.5-fold;IL-1 beta, 200-fold) and mRNA activity after stimulation was comparably higher, suggesting that increased transcription of the IL-8 gene may account for the excessive response. Using immunohistochemical staining to identify the cellular source of IL-8, activity was noted predominantly in villous and crypt epithelium but also in a few immunoresponsive lymphoid cells, The observation that immature human enterocytes react with excessive pro-inflammatory cytokine production after inflammatory stimulation may help in part explain why prematures exposed to initial colonizing bacteria develop necrotizing enterocolitis.

关键词：腺癌/病理学年龄因素细胞系结肠肿瘤/病理学十二指肠/药物作用十二指肠/胚胎学十二指肠/生长和发育十二指肠/免疫学十二指肠/代谢十二指肠/病理学小肠结肠炎坏死性/病因学孕龄革兰氏阴性菌/免疫学炎症白细胞介素1/药理学白细胞介素8/生物合成白细胞介素8/遗传学白细胞介素8/代谢肠黏膜/细胞学肠黏膜/药物作用肠黏膜/代谢脂多糖类/药理学器官培养技术 RNA 信使/生物合成肿瘤细胞培养的/药物作用肿瘤细胞培养的/代谢儿童人类

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CpG-DNA derived from sera in systemic lupus erythematosus enhances ICAM-1 expression on endothelial cells

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ANNALS OF THE RHEUMATIC DISEASES 2001年第7期60卷 685-689页

作者： Miyata, M Ito, O Kobayashi, H Sasajima, T Ohira, H Suzuki, S Kasukawa, R Fukushima Med Univ Sch Med Dept Internal Med 2 Fukushima 9601295 Japan

Objective-To examine the effect of transfection of oligodeoxynucleotides (ODNs) containing a CpG motif (CpG-ODN), of which the sequence was derived from circulating DNA in the sera of patients with systemic lupus erythematosus (SLE), on the expression of intercellular adhesion molecule-1 (ICAM-1) and synthesis of mRNA for proinflammatory cytokines and ICAM-1 in human umbilical vein endothelial cells (EC). Methods-A CpG-ODN or a control analogue, GpC-ODN, was transfected into EC. ICAM-1 expression was examined by dow cytometry, and expression of mRNA in EC encoding interleukin 1 (IL1), IL6, IL8, tumour necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma), and ICAM-1 was examined by semiquantitative reverse transcriptase-polymerase chain reaction. Results-The CpG-ODN augmented the expression of ICAM-1 on EC determined by flow cytometry and increased mRNA levels of IL6, IL8, TNF alpha, IFN gamma, and ICAM-1, but the GpC-ODN did not. Conclusion-Synthesised DNA, with a sequence corresponding to that of the fragment containing the CPG motif, in sera of patients with SLE was found to enhance ICAM-1 expression on EC, suggesting the participation of circulating DNA fragments in the pathogenesis of vasculitis in SLE.

关键词：细胞培养的 CpG岛 DNA/代谢内皮血管/免疫学脂肪酸类单不饱和/药理学流式细胞术荧光染料/药理学胞间黏附分子1/遗传学胞间黏附分子1/代谢干扰素γ/遗传学白细胞介素1/遗传学白细胞介素6/遗传学白细胞介素8/遗传学红斑狼疮系统性/遗传学红斑狼疮系统性/免疫学季胺类化合物/药理学 RNA 信使/分析逆转录聚合酶链反应肿瘤坏死因子α/遗传学人类

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