Role of tumor necrosis factor alpha in Helicobacter pylori gastritis in tumor necrosis factor receptor 1-deficient mice

Increased gastric production of interleukin 8 and tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of Helicobacter pylori-associated gastroduodenal disease. In the present study we used a mouse model to demonstrate whether loss of the tumor necrosis factor receptor 1 (TNF-R1) function leads to differences in gastric inflammation or the systemic immune response in H. pylori infection. Six different clinical isolates of H. pylori (three cytotoxin-positive and three cytotoxin-negative strains) were adapted to C57BL/6 mice. TNF-R1-deficient (TNF-R1(-/-)) mice (n = 19) and isogenetic controls (n = 24) were infected and sacrificed after 4 weeks of infection. Inflammation of the stomach and the humoral immune response to H. pylori were evaluated by histological, immunohistochemical, and serological methods. There was no detectable difference in the grade or activity of gastritis in TNF-R1(-/-) mice when they were compared with wild-type mice, but the number of lymphoid aggregates was slightly reduced in the gastric mucosa of TNF-R1(-/-) mice. Interestingly, total immunoglobulin G (IgG), as well as IgG1, IgG2b, and IgG3, H. pylori-specific antibody titers were significantly higher in wild-type mice. As revealed by immunoblot analysis, the difference in reactivity against H. pylori antigens was not based on a failure to recognize single H. pylori antigens in TNF-R1(-/-) mice. We therefore suggest that TNF-R1-mediated TNF-alpha signals might support a systemic humoral immune response against H. pylori and that the gastric inflammatory response to H. pylori infection seems to be independent of TNF-R1-mediated signals.     

Tumor necrosis factor induces tumor necrosis via tumor necrosis factor receptor type 1-expressing endothelial cells of the tumor vasculature

Activation of endothelial cells, fibrin deposition, and coagulation within the tumor vasculature has been shown in vivo to correlate with the occurrence of tumor necrosis factor (TNF)-induced tumor necrosis in mice. In the present study we investigated which target cells mediate the TNF-induced necrosis in fibrosarcomas grown in wild type (wt), TNF receptor type 1-deficient (TNFRp55-/-), and TNF receptor type 2-deficient (TNFRp75-/-) mice. TNF administration resulted in tumor necrosis exclusively in wt and TNFRp75-/-, but not in TNFRp55-/- mice, indicating a dependence of TNF-mediated tumor necrosis on the expression of TNF receptor type 1. However, using wt and TNFRp55-/- fibrosarcomas in wt mice, we found that TNF-mediated tumor necrosis was completely independent of TNF receptor type 1 expression in tumor cells. Thus we could exclude any direct tumoricidal effect of TNF in this model. Soluble TNF induced leukostasis in wt and TNFRp75-/- mice but not in TNFRp55-/- mice. TNF-induced leukostasis in TNFRp55-/- mice was restored by adoptive bone marrow transplantation of wt hematopoietic cells, but TNF failed to induce tumor necrosis in these chimeric mice. Because TNF administration resulted in both activation and focal damage of tumor endothelium, TNF receptor type 1-expressing cells of the tumor vasculature, likely to be endothelial cells, appear to be target cells for mediating TNF-induced tumor necrosis.     

Role of tumor necrosis factor alpha in pathogenesis of pneumococcal pneumonia in mice.

The production and role of tumor necrosis factor alpha (TNF-alpha) in pneumococcal pneumonia were investigated in a mouse pneumonia model. When approximately 10(6) CFU of Streptococcus pneumoniae TUM19 were used to inoculate CBA/J mice intranasally, TNF-alpha levels in the lungs and serum began to increase from 1 and 3 days after infection, respectively, concomitantly with the increase in bacterial counts in the lungs. Anti-TNF-alpha antibody accelerated bacterial proliferation in the blood and the death of the mice. Although serum levels of immunoglobulin G antibody against the infecting bacteria were not affected by the anti-TNF-alpha antibody treatment, neutrophil counts in the blood were decreased by the treatment. These results suggest that TNF-alpha produced in the course of pneumococcal pneumonia prevents bacteremia by increasing the number of neutrophils in the blood.     

Interleukin-1 and tumor necrosis factor: effector cytokines in autoimmune diseases.

Autoimmune diseases have been studied from the perspective of an abnormal immune response in genetically vulnerable hosts. Although the immune response is responsible for the initiation of autoimmune diseases, the effectors of the disease process likely involves cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF). These polypeptides induce a wide variety of inflammatory events which contribute to the destruction of tissue and tissue remodeling in several autoimmune diseases. Blocking IL-1 with its naturally occurring receptor antagonist, the IL-1 receptor antagonist reduces the severity of disease in animal models of inflammation and autoimmune processes. Clinical studies with the IL-1 receptor antagonist will define the role for this cytokine in the pathogenesis of autoimmune diseases such as arthritis, inflammatory bowel disease, type I diabetes and vasculitis.     

Acute tumor necrosis factor-alpha-induced liver injury in the absence of tumor necrosis factor receptor-associated factor 1 gene expression

Pulmonary and serum levels of tumor necrosis factor-alpha (TNF-alpha), are elevated in many lung diseases, causing local inflammation, fever, and multiorgan, including hepatic, dysfunction. Cellular responses to TNF-alpha are determined by recruitment of specific proteins to intracellular receptor signaling complexes. One of these proteins, TNF receptor-associated factor 1 (TRAF1), is highly regulated in pulmonary cells. To determine the effect of reduced pulmonary TRAF1 expression, TRAF1-null (-/-) and control, BALB/c (wild-type), mice were treated intratracheally, intraperitoneally, or intravenously, with TNF-alpha. Despite relatively mild lung injury, intratracheal TNF-alpha-treated TRAF1-/- mice exhibited marked liver injury with an approximate fivefold increase in serum liver enzyme levels as compared to wild-type mice. In addition, serum TNF-alpha levels were strikingly elevated in TRAF1-/- mice. Pretreatment with neutralizing anti-TNFRI antibody significantly reduced liver injury and serum TNF-alpha. Cells isolated by bronchoalveolar lavage from intratracheally treated TRAF1-/- mice produced more TNF-alpha than cells from treated wild-type mice, suggesting that lung cells contributed to elevated serum TNF-alpha. These studies suggest that TRAF1 provides negative feedback for TNF-alpha synthesis and limits TNFRI-mediated systemic effects of TNF-alpha originating in the lung.     

类风湿关节炎患者血清sTNF—R、TNF—α的变化

目的为探讨类风湿关节炎 (RA)与可溶性肿瘤坏死因子受体 (s TNF- R)、TNF- α、TNF- α/ s TNF- R比值的关系。方法应用双抗体夹心 EL ISA法检测了活动期 RA(2 8例 ) ,稳定期 RA (12例 )及健康人 (30例 )血清中 s TNF- R 、s TNF- R 、TNF-α的水平。结果活动期 RA患者血清 s TNF- R 、s TNF- R 、TNF-α水平明显高于健康人及稳定期 RA组 ,P均 <0 .0 1。稳定期 RA患者血清 s TNF- R 、s TNF- R 、TNF-α水平亦明显高于健康人 ,P<0 .0 1。在 RA患者中 ,血清 s TNF- R 、s TNF- R 水平与 ESR、CRP、Ritchie index呈显著正相关 ,与类风湿因子 (RF)水平无相关性。RA患者治疗 3个月后 s TNF- R 、s TNF- R 及 TNF- α/ s TNF R比值显著下降。结论 RA患者血清 s TNF- R 、s TNFR- 水平显著增高 ,且与疾病活动度呈正相关。测定血清 s TNF- R 、s TNF- R 、TNF- α/ s TNF- R水平可作为 RA诊断 ,监测疾病活动、治疗及判断预后的一项有意义的实验室指标     

Interferon alpha induction of metallothionein in rat liver is not linked to interleukin-1, interleukin-6, or tumor necrosis factor alpha

Synthesis of metallothionein (MT) is induced by interferon-alpha (IFN-alpha) in vitro and in vivo. In addition, IFN-alpha promotes redistribution of zinc (Zn) from the plasma to the liver in mice. However, it is not clear if IFN-alpha induces hepatic MT synthesis directly or indirectly via liberation of other cytokines. In order to address this issue, we determined hepatic MT levels, Zn concentration in plasma, liver, and urine, and plasma levels interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) in rats following intramuscular injection of human IFN-alpha (1.5 x 10(6) UI/m(2)). Animals were housed in metabolic cages and sacrificed at various times after IFN-alpha administration. Zn concentrations in serum, urine, and hepatic tissue were determined by atomic absorption spectrophotometry. MT protein was measured using the MT silver saturation method and expression of MT-1 and MT-2 mRNA was measured by RT-PCR. Plasma levels of rat IL-1, IL-6, and TNFalpha were determined using an ELISA method. Hepatic MT levels began to increase at 2 h following IFN-alpha administration and reached maximum levels at 12 h post-treatment. Induction of MT gene expression was confirmed by increases in MT-1 and MT-2 mRNA levels 6, 12, and 18 h after IFN-alpha administration. IFN-alpha treatment also resulted in biphasic increases in hepatic Zn, with levels peaking at 2 h, the time-point when MT levels are first increased, and again at 18 h. Concurrently, there were decreases in serum Zn levels at these time points, suggesting IFN-alpha induced movement of Zn from the blood to hepatic tissue. The decrease in serum Zn was not due to increased excretion since urinary Zn levels were unaffected following IFN-alpha treatment. IFN-alpha administration had no effect on plasma IL-1, IL-6, and TNFalpha levels. These results show that IFN-alpha promotes the increase of hepatic MT levels and plasma/liver redistribution directly, without IL-1, IL-6, or TNFalpha participation.     

Role of tumor necrosis factor alpha in asthma

Asthma is a heterogeneous disease in which various cytokines orchestrate airway inflammation. Tumor necrosis alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in the modulation of inflammation in various diseases, including asthma. Although TNF-alpha blocking strategies have been an effective therapeutic modality in diseases such as rheumatoid arthritis, their role in asthma and the effects of the blockade in asthma is poorly understood. This article examines the role of TNF-alpha in asthma and the effects of blocking TNF-alpha as a possible therapeutic option in patients with severe corticosteroid-dependent asthma.     

Interleukin-1 alpha and tumor necrosis factor alpha cause placental injury in the rat.

Bacterial endotoxins (LPS) causes placental injury and fetal demise in pregnant animals. Because several biological effects of LPS are mediated by interleukin-1 (IL-1) and tumor necrosis factor (TNF), the hypothesis that these cytokines could cause placental injury similar to that seen in LPS-treated pregnant rats was tested. On day 12 of gestation, rats were injected intraperitoneally with saline, LPS, native or heat-inactivated (HI) rHIL 1 alpha, or rH-TNF alpha. Seven days later, grossly abnormal implantation sites and fetal demise were observed in rats injected with rHIL-1, rHTNF, or LPS but not in those injected with saline or HI-cytokines. Necrosis of placental, decidual, and fetal tissues was observed in cytokine-treated animals. The necrosis was more severe in LPS-treated rats, in which no fetal remains were identifiable. These data suggest that IL-1 and TNF may play a role in the fetoplacental injury observed in LPS-treated pregnant rats.     

Intercellular adhesion molecule 1 and tumor necrosis factor alpha in asthma and persistent allergic rhinitis: relationship with disease severity.

BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is involved in the up-regulation of intercellular adhesion molecule 1 (ICAM-1). Allergic rhinitis is often associated with bronchial hyperresponsiveness. OBJECTIVE: We investigated the relationship between allergic airway disease severity and serum concentrations of soluble ICAM-1 (sICAM-1) and TNF-alpha and nasal expression of ICAM-1. METHODS: Serum concentrations of TNF-alpha and sICAM-1 were investigated in 85 adults with persistent rhinitis and 90 patients with asthma. Seventy patients with rhinitis were challenged with methacholine. Nasal biopsy for ICAM-1 expression was performed in 6 patients with moderate-severe rhinitis and in 6 patients with mild rhinitis. RESULTS: In patients with rhinitis, serum sICAM-1 concentrations were as follows: group without bronchial hyperresponsiveness (n = 29), 206.85 ng/mL; group with bronchial hyperresponsiveness but without asthma symptoms (n = 20), 233.39 ng/mL; and group with newly recognized asthma (n = 21), 260.06 ng/mL. The sICAM-1 level was significantly lower in patients with mild rhinitis (216.21 ng/mL) than in patients with moderate-severe rhinitis (244.08 ng/mL). Nasal ICAM-1 expression was significantly higher in the moderate-severe rhinitis group than in the mild rhinitis group. In patients with asthma, serum concentrations of sICAM-1 were as follows: patients with mild asthma, 272.8 ng/mL; patients with moderate asthma, 340.16 ng/mL; patients with severe asthma without oral corticosteroids therapy, 426.74 ng/mL; and patients with severe asthma with oral corticosteroids therapy, 314 ng/mL. The serum TNF-alphaa concentration differed between patients with rhinitis (n = 15) (1.065 pg/mL) and patients with asthma (n = 12) (3.46 pg/mL). Among patients with asthma, TNF-alpha concentrations were similar in all groups classified according to the disease severity. CONCLUSIONS: sICAM and ICAM-1 expression correlates with airways diseases severity.     

Interleukin-1 and tumor necrosis factor synergistically stimulate lung fibroblast interleukin-1 alpha production

We determined whether normal human lung fibroblasts expressed cell-associated thymocyte-stimulating activity in response to recombinant interleukin-1 (rIL-1) (alpha and beta) and recombinant tumor necrosis factor (rTNF). Individually, rIL-1 and rTNF induced fibroblast expression of thymocyte-stimulating activity, with rIL-1 being significantly more potent. Importantly, combining rIL-1 and rTNF resulted in a synergistic increase in fibroblast thymocyte-stimulating activity. This synergistic interaction was dose dependent for both cytokines and was not noted when gamma-interferon was combined with rIL-1 or rTNF. In all cases, the thymocyte-stimulating activity was the result of an IL-1 alpha-like moiety whose maximal production required protein synthesis. IL-1 alpha activity could be detected after as little as 4 h, peaked after 24 h, and returned toward normal with longer periods of cytokine-fibroblast incubation. However, cytokine-stimulated fibroblasts that no longer expressed IL-1 alpha activity could be induced to re-express this activity with repeat cytokine challenge. Induction of fibroblast IL-1 alpha by IL-1 and/or TNF may be an important mechanism amplifying IL-1-mediated biologic events at sites of local inflammation.     

终末期肾病患者肿瘤坏死因子α基因多态性与微炎症状态的相关性研究

目的探讨肿瘤坏死因子(TNF-α)基因G-308A位点的遗传多态性和终末期肾病(ESRD)患者微炎症状态的相关关系。方法采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)检测30例健康对照者、60例终末期肾病患者该位点的基因多态性;应用ELISA测定血清C反应蛋白(CRP)、TNF-α浓度。结果 TNF-α-308AG+AA基因型在ESRD组、健康对照组分布频率分别为12%、7%,两组在基因型分布频率、等位基因频率差异均无统计学意义。ESRD组的不同基因型血清CRP、TNF-α浓度未发现差异;ESRD患者血清CRP、TNF-α浓度与基因型之间的Spearman相关系数分别为0.101和0.09(P0.05)。结论 TNF-α基因G-308A位点的基因多态性与ESRD的发生无相关性。ESRD患者血清CRP、TNF-α浓度升高与TNF-α基因G-308A位点的基因多态性无关。     

Immunobiology of tumor necrosis factor receptor superfamily

The proteins of the tumor necrosis factor (TNF) receptor superfamily are a group of cell-surface receptors critically involved in the maintenance of homeostasis of the immune system. By interacting with their corresponding ligands, these receptors either induce cell death or promote cell survival of immune cells. The number of recognized members of the TNF receptor and ligand superfamily has expanded substantially in the last several years. More important, the biologic function of this group of proteins has been closely associated with the regulation of the immune response and the pathogenesis of autoimmune disease. Thus, the direct targeting of these receptors by either inducing apoptosis or blocking survival of autoimmune T and B cells may be an important therapeutic strategy in the treatment of autoimmune disease. This review summarizes the recent progress in immunobiology of the TNF receptor superfamily and focuses on our studies of three critical family members-FasL/Fas, TNF-related apoptosis-inducing ligand (TRAIL)/TRAIL-Rs, and B lymphocyte stimulator(BLyS)/BLyS-Rs--to demonstrate the therapeutic potential of targeting these receptors for the treatment of autoimmune disease.     

Chlamydiae modulate gamma interferon, interleukin-1 beta, and tumor necrosis factor alpha receptor expression in HeLa cells

Chlamydia psittaci was found to modulate receptor expression for the cytokine receptors that are involved in the synergistic induction of indoleamine dioxygenase in epithelial cells. Increases in receptor expression were seen even with inactivated Chlamydia, suggesting that chlamydial antigens and not products of infection are important for up-regulating cytokine receptor expression.     

Inhibitory effect of suramin on receptor binding and cytotoxic activity of tumor necrosis factor alpha.

The effect of suramin on the binding of human Tumor Necrosis Factor alpha (huTNF alpha) to specific cell-surface receptors as well as on its cytotoxic activity in vitro was investigated. Suramin inhibited both activities in a dose-dependent manner. Experiments designed to discriminate if suramin exerted its inhibitory activity on the ligand or on the receptor showed that the ligand (huTNF alpha) was the most likely target for suramin in this system. These results may explain, in part, the immunosuppressive activities of suramin that have been observed in vivo and suggest that suramin could be useful in those disease states in which hyperproduction of huTNF alpha has been shown to play a pathogenic role.     

异搏定和肿瘤坏死因子α协同抗肿瘤作用的实验研究

目的:研究异搏定和肿瘤坏死因子α(TNFα)对肝癌的协同作用。方法:利用人肝癌HepG₂体外培养及裸鼠皮下移植模型,在异搏定、肿瘤坏死因子以及异搏定和肿瘤坏死因子同时存在的条件下,观察肿瘤细胞增殖及肿瘤组织生长状况、c-myc表达肿瘤组织的细胞增殖核抗原(PCNA)检验以及肿瘤组织微血管密度(MVD)的比较。结果:在异搏定以及异搏定和TNFα同时存在的条件下,HepG₂的增殖及移植肿瘤的生长受到明显抑制;c-myc的表达、PCNA的表达以及MVD明显降低。结论:钙通道阻滞剂可抑制肿瘤的增殖与生长;异搏定与TNFα有显著的协同抗肿瘤作用。