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Platelet-derived growth factor induces interleukin-6 transcription in osteoblasts through the activator protein-1 complex and activating transcription factor-2

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第10期274卷 6783-6789页

作者： Franchimont, N Durant, D Rydziel, S Canalis, E St Francis Hosp & Med Ctr Res Dept Worcester MA 01605 USA St Francis Hosp & Med Ctr Dept Med Worcester MA 01605 USA Univ Connecticut Sch Med Farmington CT 06030 USA

Platelet-derived growth factor (PDGF) BE, a mitogen that stimulates bone resorption, increases the expression of interleukin-6 (IL-6), a cytokine that induces osteoclast recruitment. The mechanisms involved in IL-6 induction by PDGF BE are poorly understood. We examined the effect of PDGF BE on IL-6 expression in cultures of osteoblasts from fetal rat calvariae (Ob cells). PDGF BE increased IL-6 mRNA and heterogeneous nuclear RNA levels, the rate of transcription, and the activity of base pairs (bp) -2906 to +20 IL-6 promoter fragments transiently transfected into Ob cells. Deletion analysis revealed two responsive regions, one containing an activator protein-1 (AP-1) site located between bp -276 and -257, and a second, less well defined, downstream of -257. Targeted mutations of a cyclic AMP-responsive element (CRE), and nuclear factor-IL-6 and nuclear factor-kappa B binding sites in a bp -257 to +20 IL-6 construct that was transfected into Ob cells, revealed that the CRE also contributed to IL-6 promoter induction by PDGF BE. Electrophoretic mobility shift assay revealed AP-1 and CRE nuclear protein complexes that were enhanced by PDGF BE. Supershift assays revealed binding of Jun and Fos to AP-1 and CRE sequences and binding of activating transcription factor-a to CRE. In conclusion, PDGF BE induces IL-6 transcription in osteoblasts by regulating nuclear proteins of the AP-1 complex and activating transcription factor-2.

关键词：转录激活因子2 cAMP反应元件结合蛋白质/遗传学 cAMP反应元件结合蛋白质/代谢白细胞介素6/生物合成白细胞介素6/遗传学成骨细胞/代谢血小板源性生长因子/药理学 RNA 信使/分析 RNA 信使/生物合成信号传导/药物作用信号传导/遗传学转录因子AP-1/遗传学转录因子AP-1/代谢转录因子/遗传学转录因子/代谢转录遗传/药物作用动物大鼠

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Activation of primary human monocytes by the oxidized form of α1-antitrypsin

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第11期275卷 7693-7700页

作者： Moraga, F Janciauskiene, S Malmo Univ Hosp Dept Med Gastroenterol Hepatol Sect S-20502 Malmo Sweden

The oxidation of methionine residues in many proteins, including the serine proteinase inhibitor alpha 1-antitrypsin (AAT), can result in functional inactivation. In this study we investigated the pro-inflammatory properties of oxidized AAT (oxAAT), specifically its ability to activate human monocytes in culture. Monocytes stimulated with oxAAT at concentrations up to 0.2 mg/ml for 24 h showed significant elevation in monocyte tractant;tractant protein-1, cytokine interleukin-6, and tumor necrosis factor-a expression and increased NADPH oxidase activity. Monocytes activated with oxAAT showed surprising effects on lipid metabolism. Expression of low density lipoprotein (LDL) receptors increased by up to 76% compared with controls but was not accompanied by any changes in I-125-labeled LDL binding and, paradoxically, decreased LDL uptake, degradation, and intracellular cholesterol synthesis. oxAAT also down-regulated the scavenger receptor CD36, which takes up and is up-regulated by oxidized LDL and is down-regulated by cholesterol efflux, As a by-product of oxidative events accompanying inflammation, oxAAT has multiple effects on cytokine expression, generation of reactive oxygen species,and on intracellular lipid metabolism. The up-regulation of monocyte-derived reactive oxygen by oxAAT could potentially result in self-amplification of AAT oxidation and, thereby, the other effects deriving from it. This implies that there are as yet unidentified regulatory processes that control this cycle.

关键词：趋化因子CCL2/生物合成胆固醇/生物合成减量调节酶激活炎症介导素类/代谢白细胞介素6/生物合成脂蛋白类 LDL/代谢膜蛋白质类单核细胞/药物作用氧化还原受体免疫/生物合成受体 LDL/生物合成受体脂蛋白受体清道夫清道夫受体 B类肿瘤坏死因子α/生物合成 α1抗胰蛋白酶/化学 α1抗胰蛋白酶/药理学人类

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Interleukin-6 production by endothelial cells after infection with influenza virus and cytomegalovirus

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JOURNAL OF LABORATORY AND CLINICAL MEDICINE 1999年第6期134卷 623-630页

作者： Visseren, FLJ Verkerk, MSA Bouter, KP Diepersloot, RJA Erkelens, DW Univ Utrecht Hosp Dept Internal & Vasc Med NL-3584 CX Utrecht Netherlands Diakonessen Hosp Utrecht Dept Microbiol Utrecht Netherlands Den Bosch Bosch Med Ctr Dept Internal Med Utrecht Netherlands

Inflammation plays a role in the pathogenesis of cardiovascular diseases. Viruses may be a cause of chronic inflammation, and both influenza virus and CMV have been associated with cardiovascular diseases. IL-6, a proinflammatory cytokine with antiviral effects, has a pivotal role in the Immune response, and under pathologic conditions, prohemostatic effects of IL-6 could lead to pathologic thrombosis and vascular plaque instability. To investigate this role of IL-6, we measured the production of IL-6 by human endothelial cells after infection with influenza virus and CMV. After infection with influenza virus or CMV, IL-6 release into the medium increased (1756.5 +/- 156.9 pg/mL vs 284.4 +/- 55.3 pg/mL;P < .001) for influenza-infected compared with uninfected cells after 36 hours' incubation. Ultracentrifuged influenza virus supernatants, heat-inactivated virus, and purified hemagglutinin were not able to elicit IL-6 synthesis by human endothelial cells. These findings show that CMV and influenza virus are capable of modulating the in vitro production of IL-6, a cytokine involved in vascular inflammation, by human endothelial cells.

关键词：细胞培养的巨细胞病毒/生理学内皮血管/代谢内皮血管/病毒学流感病毒A型/生理学白细胞介素6/生物合成 L-乳酸脱氢酶/代谢显微镜检查相差脐静脉/细胞学人类

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Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells

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BLOOD 2000年第3期95卷 999-1006页

作者： Decker, T Schneller, F Sparwasser, T Tretter, T Lipford, GB Wagner, H Peschel, C Tech Univ Munich Dept Med 3 D-81675 Munich Germany Tech Univ Munich Inst Med Microbiol & Hyg D-81675 Munich Germany

Bacterial DNA and synthetic CpG-oligodeoxynucleotides (ODNs) derived thereof have attracted attention because they activate cells of the immune system in a sequence-dependent manner. Here we investigated the potential of CpG-ODNs to cause proliferation, cytokine production, and regulation of surface molecules in human B-chronic lymphocytic leukemia (CLL) cells, CpG-ODN induced proliferation in both B-CLL cells and normal B cells;however, only B-CLL cells increased proliferative responses when CpG-ODN was added to co-cultures of CD40-ligand transfected mouse fibro blasts (CD40LF) and B cells, Production of interleukin-6 and tumor necrosis factor a was detectable at borderline levels, using CpG-ODN as the only stimulus, In contrast, when CpG-ODN was added to co-cultures of B cells and CD40LF, a strong increase in cytokine production occurred in B-CLL cells as well as in normal B cells, The surface molecules CD40, CD58, CD80, CD86, CD54, and MHC class I molecules were up-regulated in B-CLL cells, whereas CD95 expression was not influenced by CpG-ODN stimulation, The same pattern of surface molecule regulation was observed in normal B cells, but up-regulation of CD40 was significantly stronger in B-CLL cells, Costimulation with CpG-ODN and CD40LF resulted in further up-regulation of CD58, CD80, CD86, and MHC class I molecules, In contrast, CD95 expression induced by CD40-ligation was inhibited by CpG-ODN. CpG-ODN activated B-CLL cells acquired a strong stimulatory capacity toward T cells in allogeneic mixed lymphocyte reaction, This effect was completely inhibited by a combination of anti-CD80 and anti-CD86 monoclonal antibody. Taken together, these findings suggest the possible use of CpG-ODN for immunotherapeutic strategies in patients with B-CLL. (C) 2000 by The American Society of Hematology.

关键词：佐剂免疫/药理学抗原 CD/生物合成抗原 CD/遗传学抗原 CD/免疫学抗原 CD40/免疫学抗原 CD80/免疫学抗原 CD86 抗原肿瘤/生物合成抗原肿瘤/遗传学 B淋巴细胞亚群/细胞学 B淋巴细胞亚群/药物作用 B淋巴细胞亚群/代谢 CD40配体细胞分裂/药物作用共同培养技术细胞因子类/生物合成细胞因子类/遗传学成纤维细胞基因表达调控白血病/药物作用基因 MHCⅠ类组织相容性抗原Ⅰ类/生物合成免疫表型分型白细胞介素6/生物合成白细胞介素6/遗传学淋巴细胞协同作用淋巴细胞培养试验混合膜糖蛋白类/遗传学膜糖蛋白类/免疫学寡脱氧核糖核苷酸类/药理学转染肿瘤细胞培养的肿瘤坏死因子α/生物合成肿瘤坏死因子α/遗传学动物人类小鼠

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Activation of p38 mitogen-activated protein kinase and c-Jun NH₂-terminal kinase by double-stranded RNA and encephalomyocarditis virus:: Involvement of RNase L, protein kinase R, and alternative pathways

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MOLECULAR AND CELLULAR BIOLOGY 2000年第2期20卷 617-627页

作者： Iordanov, MS Paranjape, JM Zhou, AM Wong, J Williams, BRG Meurs, EF Silverman, RH Magun, BE Oregon Hlth & Sci Univ Dept Cell & Dev Biol Portland OR 97201 USA Cleveland Clin Fdn Lerner Res Inst Dept Canc Biol Cleveland OH 44195 USA Inst Pasteur Unite Virol & Immunol Cellulaire F-75724 Paris 15 France

Double-stranded RNA (dsRNA) accumulates in virus-infected mammalian cells and signals the activation of host defense pathways of the interferon system, We describe here a novel form of dsRNA-triggered signaling that leads to the stimulation of the p38 mitogen-activated protein kinase (p38 MAPK) and the c-Jun NH,terminal kinase (JNK) and of their respective activators MKK3/6 and SEK1/MKK4. The dsRNA-dependent signaling to p38 MAPK was largely intact in cells lacking both RNase L and the dsRNA-activated protein kinase (PKR), i.e., the two best-characterized mediators of dsRNA-triggered antiviral responses. In contrast, activation of both MKK4 and JNK by dsRNA was greatly reduced in cells lacking RNase L (or lacking both RNase L and PKR) but was restored in these cells when introduction of dsRNA was followed by inhibition of ongoing protein synthesis or transcription. These results are consistent with the notion that the role of RNase L and PKR in the activation of MKK4 and JNK is the elimination, via inhibition of protein synthesis, of a labile negative regulator(s) of the signaling to JNK acting upstream of SEK1/MKK4, In the course of these studies, we identified a long-sought site of RNase L-mediated cleavage in the 28S rRNA, which could cause inhibition of translation, thus allowing the activation of JNK by dsRNA, We propose that p38 MAPK is a general participant in dsRNA-triggered cellular responses, whereas the activation of JNK might be restricted to cells with reduced rates of protein synthesis. Our studies demonstrate the existence of alternative (RNase L- and PKR-independent) dsRNA-triggered signaling pathways that lead to the stimulation of stress-activated MAPKs. Activation of p38 MAPK (but not of JNK) was demonstrated in mouse fibroblasts in response to infection with encephalomyocarditis virus (ECMV), a picornavirus that replicates through a dsRNA intermediate. Fibroblasts infected with EMCV (or treated with dsRNA) produced interleukin-6, an inflammatory

关键词：细胞系脑心肌炎病毒/遗传学脑心肌炎病毒/生理学内切核糖核酸酶类/遗传学内切核糖核酸酶类/代谢酶激活/药物作用成纤维细胞基因缺失白细胞介素6/生物合成 JNK丝裂原活化蛋白激酶类 MAP激酶信号系统/药物作用丝裂原激活蛋白激酶类/代谢模型生物学磷酰化/药物作用蛋白质生物合成/药物作用蛋白质生物合成/遗传学蛋白质合成抑制药/药理学 RNA 双链/遗传学 RNA 双链/药理学 RNA 双链/生理学 RNA 核糖体 28S/遗传学 RNA 核糖体 28S/代谢阻遏蛋白质类/代谢 eIF-2激酶/遗传学 eIF-2激酶/代谢 p38丝裂原活化蛋白激酶类动物人类小鼠大鼠

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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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Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin-4 selectively induces expression of vascular cell adhesion molecule-1 and P-selectin resulting in preferential adhesion of lymphocytes

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IMMUNOLOGY 2000年第4期100卷 441-448页

作者： Kotowicz, K Dixon, GLJ Klein, NJ Peters, MJ Callard, RE Inst Child Hlth Immunobiol Unit London WC1N 1EH England

The expression of adhesion molecules on vascular endothelial cells determines the pattern of migration and extravasation of leucocytes in inflammation and immunity. Here we show that costimulation with CD40 ligand (CD40L) and interleukin (IL)-4 (or IL-13) gives rise to a unique pattern of adhesion molecule expression by human umbilical vein endothelial cells (HUVEC). CD40 ligation alone enhanced expression of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin whereas IL-4 and IL-13 increased expression of VCAM-1 and P-selectin but not ICAM-1 or E-selectin. When IL-4 and CD40L were combined there was an additional increase of both VCAM-1 and P-selectin, but ICAM-1 and E-selectin were both inhibited. The combined effects of IL-4 and CD40L signalling were not the result of altered response kinetics, enhanced sensitivity of the endothelium, or increased expression of CD40 or the IL-4 receptor. The rise in VCAM-1 expression induced by combined IL-4 and CD40L stimulation was slower and more sustained than with tumour necrosis factor-alpha (TNF-alpha) and occurred only on a subset (75-80%) of the endothelial cell population compared to 100% with TNF-alpha. Costimulation with IL-4 and CD40L increased adhesion of T cells and B cells above levels obtained with either signal alone, but decreased adhesion of neutrophils. Furthermore, CD40 and IL-4 synergistically increased IL-6 but decreased IL-8 production by HUVEC. These results show that interactions between IL-4 and CD40 on endothelial cells give rise to specific patterns of adhesion molecule expression and cytokine production that may have important implications for lymphocyte and neutrophil migration and function at sites of inflammation.

关键词： CD40配体细胞黏附/免疫学细胞培养技术 E选择素/代谢内皮血管/免疫学胞间黏附分子1/代谢白细胞介素4/免疫学白细胞介素6/生物合成白细胞介素8/生物合成配体淋巴细胞/免疫学膜糖蛋白类/代谢中性白细胞/免疫学 P选择素/代谢血管细胞黏附分子1/代谢人类

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Introduction: the evolving role of bisphosphonate therapy in multiple myeloma

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BLOOD 2000年第2期96卷 381-383页

作者： Raje, N Anderson, KC Dana Farber Canc Inst Boston MA 02115 USA

Bone disease is a hallmark of multiple myeloma (MM) and contributes to most of the debilitating morbidity associated with this disease. Bone lesions result not only from the direct deposits of MM cells within the bone, but also from the release of soluble factors by both the tumor and the microenvironment, resulting in the stimulation of osteoclast activity and bone resorption. The use of pharmacologic intervention with bisphosphonate therapy has resulted in a significant reduction in skeletally related events such as the occurrence of pathologic fractures, lytic lesions, bone pain, and hypercalcemia. In addition, their use has been recently shown to provide a survival benefit in a subset of MM patients. In this issue of Blood, Kunzmann et al1 reveal a novel antitumor effect of aminobisphosphonates through their stimulation of γδT cells and the induction of an anti-MM activity in patient samples. Their study is a seminal finding and possibly reflects an alternative mechanism by which these drugs might play an immunomodulatory role in MM.

关键词：抗肿瘤药/治疗应用骨质吸收/病因学骨质吸收/预防和控制二膦酸盐类/治疗应用白细胞介素6/拮抗剂和抑制剂白细胞介素6/生物合成多发性骨髓瘤/并发症多发性骨髓瘤/药物疗法破骨细胞/生理学人类

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Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis:: potential implications for treatment

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ANNALS OF THE RHEUMATIC DISEASES 2000年第6期59卷 439-447页

作者： Ulfgren, AK Gröndal, L Lindblad, S Khademi, M Johnell, O Klareskog, L Andersson, U Karolinska Hosp Rheumatol Res Lab Dept Med Rheumatol Unit S-17176 Stockholm Sweden Karolinska Hosp Unit Neuroimmunol S-17176 Stockholm Sweden Univ Uppsala Hosp Dept Orthopaed Surg Uppsala Sweden Malmo Univ Hosp Dept Orthopaed Malmo Sweden Astrid Lindgrens Childrens Hosp Dept Rheumatol Stockholm Sweden

Objectives-Assessment of the numbers and spatial distribution of cells producing interleukin 1 alpha (IL1 alpha), interleukin 1 beta (IL1 beta), tumour necrosis factor alpha (TNF alpha), and interleukin 6 (IL6) in the synovial membranes of patients with rheumatoid arthritis (RA). Methods-Synovial tissue specimens from 40 patients with RA and eight patients with non-rheumatic disease were obtained by arthroscopy guided biopsy techniques or during joint surgery. A modified immunohistochemical method detecting cytokine producing rather than cytokine binding cells was applied to determine cytokine synthesis in fixed cryopreserved sections. Computerised image analysis methods provided comparative quantitative assessments. Results-A wide variation between subjects was recorded for both quantities and profiles of expressed cytokines, despite similar macroscopic and histopathological features of inflammation. IL1 alpha and IL1 beta were the most abundant monokines identified, though produced at different sites. IL1 alpha was predominantly seen in vascular endothelial cells, whereas IL1 beta staining was mainly shown in macrophages and fibroblasts. Concordant results for the detection of TNF alpha at protein and mRNA levels were obtained with an unexpectedly low number of TNF alpha producing cells compared with IL1 expressing cells in many patients with RA. Specimens acquired arthroscopically from areas with maximum signs of macroscopic inflammation showed an increased number of TNF alpha producing cells in pannus tissue compared with that occurring in synovial villi of a given joint. This clustered distribution was not found for cells expressing any of the other studied cytokines. Conclusion-The recorded heterogeneous profile of proinflammatory cytokine synthesis in the synovial membrane among patients with RA may provide a clue for an understanding of the wide variation in responsiveness to different modes of antirheumatic treatment between patients.

关键词：关节炎类风湿/免疫学关节炎类风湿/病理学关节镜检查病例对照研究细胞计数图像处理计算机辅助免疫组织化学白细胞介素1/分析白细胞介素1/生物合成白细胞介素6/分析白细胞介素6/生物合成统计学非参数滑膜/免疫学肿瘤坏死因子α/分析肿瘤坏死因子α/生物合成成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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