P55 Tumor Necrosis Factor Research Articles

Respiratory Burst and TNF-α Receptor Expression of Neutrophils after Sepsis and Severe Injury-Induced Inflammation in Children.

Systemic inflammatory response syndrome (SIRS) is defined as the systemic host response to infection or a non-infectious factor. The purpose of this study was to evaluate the involvement of reactive oxygen species (ROS) in severe inflammation and to assess the discrimination strength of the neutrophil BURSTTEST assay regarding its etiology in three groups of patients (sepsis, burns, and bone fractures) who met the SIRS criteria. The neutrophil activation (respiratory burst of granulocytes as well as p55 and p75 tumor necrosis factor (TNF-α) receptor expression) was evaluated twice using flow cytometry, and the results were compared with healthy controls and among SIRS subjects. A decreased oxygen metabolism in neutrophils after E. coli stimulation and increased TNF-α receptor expression were found in septic and burned patients on admission, while ROS production augmented and TNF-α receptor expression diminished with the applied therapy. The significant differences in neutrophil respiratory burst intensity among septic and burned patients and those with sepsis and bone fractures were found (however, there were not any such differences between patients with thermal and mechanical injuries). This study indicates that the neutrophil BURSTTEST evaluation might be a clinically reliable marker for differentiating the SIRS etiology.

Circadian rhythms of factors involved in luteal regression are modified in p55 tumour necrosis factor receptor (TNFRp55)-deficient mice.

The rhythm of factors involved in luteal regression is crucial in determining the physiological duration of the oestrous cycle. Given the role of tumour necrosis factor (TNF)-α in luteal function and circadian regulation and that most of the effects of TNF-α are mediated by p55 TNF receptor (TNFRp55), the aims of the present study were to analyse the following during the luteal regression phase in the ovary of mice: (1) whether the pattern of expression of progesterone (P4) and the enzymes involved in the synthesis and degradation of P4 is circadian and endogenous (the rhythm persists in constant conditions, (i.e., constant darkness) with a period of about 24 hours); (2) circadian oscillations in clock gene expression; (3) whether there are daily variations in the expression of key genes involved in apoptosis and antioxidant mechanisms; and (4) the consequences of TNFRp55 deficiency. P4 was found to oscillate circadianally following endogenous rhythms of clock factors. Of note, TNFRp55 deficiency modified the circadian oscillation in P4 concentrations and its enzymes involved in the synthesis and degradation of P4, probably as a consequence of changes in the circadian oscillations of brain and muscle ARNT-Like protein 1 (Bmal1) and Cryptochrome 1 (Cry1). Furthermore, TNFRp55 deficiency modified the circadian rhythms of apoptosis genes, as well as antioxidant enzymes and peroxidation levels in the ovary in dioestrus. The findings of the present study strengthen the hypothesis that dysregulation of TNF-α signalling may be a potential cause for altered circadian and menstrual cycling in some gynaecological diseases.

Severity of Plasma Leakage Is Associated With High Levels of Interferon γ-Inducible Protein 10, Hepatocyte Growth Factor, Matrix Metalloproteinase 2 (MMP-2), and MMP-9 During Dengue Virus Infection.

Dengue virus infection typically causes mild dengue fever, but, in severe cases, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) occur. The pathophysiological hallmark of DHF and DSS is plasma leakage that leads to enhanced vascular permeability, likely due to a cytokine storm. Ninety patients with dengue during 2010-2012 in Singapore were prospectively recruited and stratified according to their disease phase, primary and secondary infection status, and disease severity, measured by plasma leakage. Clinical parameters were recorded throughout the disease progression. The levels of various immune mediators were quantified using comprehensive multiplex microbead-based immunoassays for 46 immune mediators. Associations between clinical parameters and immune mediators were analyzed using various statistical methods. Potential immune markers, including interleukin 1 receptor antagonist, interferon γ-inducible protein 10, hepatocyte growth factor, soluble p75 tumor necrosis factor α receptor, vascular cell adhesion molecule 1, and matrix metalloproteinase 2, were significantly associated with significant plasma leakage. Secondary dengue virus infections were also shown to influence disease outcome in terms of disease severity. This study identified several key markers for exacerbated dengue pathogenesis, notably plasma leakage. This will allow a better understanding of the molecular mechanisms of DHF and DSS in patients with dengue.

Positive feedback role of TRPC3 in TNF-α-mediated vasogenic edema formation induced by status epilepticus independent of ETB receptor activation

Brain–blood barrier (BBB) disruption results in vasogenic edema, which is involved in the pathogenesis of epilepsy. Following status epilepticus (SE), up-regulated transient receptor potential canonical channel-3 (TRPC3), a Ca2+-permeable cation channels in endothelial cells, is relevant to vasogenic edema formation in the rat piriform cortex. In addition, pyrazole-3 (Pyr-3, a TRPC3 inhibitor) attenuated SE-induced vasogenic edema. However, the upstream regulators of TRPC3 expression in vasogenic edema formation have been unclear. In the present study, soluble tumor necrosis factor p55 receptor (sTNFp55R, a TNF-α inhibitor), SN50 (a nuclear factor-κB (NFκB) inhibitor), BQ-788 (an endothelin B (ETB) receptor inhibitor) and Pyr-3 effectively prevented vasogenic edema following SE. sTNFp55R and SN50 (but not BQ-788) attenuated SE-induced up-regulation of endothelial TRPC3 expression. Pyr-3 ameliorated SE-induced NFκB p65-Thr435 phosphorylation and ETB receptor expression. In addition, Pyr-3 mitigated NFκB p65-Thr435 phosphorylation induced by recombinant TNF-α. These findings indicate that TNF-α-mediated NFκB p65-Thr435 phosphorylation may up-regulate TRPC3 expression, which participates in vasogenic edema formation via increasing endothelial nitric oxide synthase expression following SE, independent of ETB receptor activation. Therefore, we suggest that TRPC3 may be involved in a positive feedback loop of NFκB/ETB receptor signaling pathway.

Protection against myocardial ischemia -reperfusion injury in rats by a novel selective lymphotoxin binding p55TNFR

Objective To investigate the effect of a novel lymphotoxin with selectively binding to p55 tumor necrosis factor receptor (p55TNFR) on myocardial ischemia -reperfusion injury in rats in order to explore the mechanism. Methods A total of 40 SD rats were randomly (random number) assigned into four groups (n =10 in each) , namely sham operation group (group A), I/R group (group B), wild type rhLTα treatment group (group C), and p55TNFR selective rhLTα (rhLTα-Q107E) treatment group (group D). After I/R model rats were established, various therapeutic agents or saline were given by continuous intravenous infusion for 24 h via a micropump. After 24 hours of treatment, serum myocardial zymogram, such as aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase (CK), as well as superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) activities were determined. Myocardial infarction size (MIS) was measured by nitro blue tetrazolium chloride (NBT) staining. Results Compared to sham operation group, MIS, AST, LDH, CK, MDA were increased, while the activities of SOD and GSH-Px were decreased. However, all the effects were significantly reversed by treatment with rhLTα-Q107E (P 0.05). Conclusions The rhLTα-Q107E plays a role in the protection against myocardial ischemia -reperfusion injury in rats by the mechanism of scavenging oxygen free radicals and increasing the activity of endogenous antioxidant system. Key words: p55TNFR; Ischemia-reperfusion; Myocardial injury; Oxidative stress

Therapeutic effects of p75 tumor necrosis factor receptor monoclonal antibody on a rat model of traumatic arthritis

BackgroundThe aim of the present study was to investigate the therapeutic effects of p75 tumor necrosis factor receptor monoclonal antibody D8F2 on a traumatic arthritis model in rats, and to explore the underlying mechanism. MethodsForty male Sprague Dawley rats were randomly divided into five groups: (A) sham operation control group, (B) traumatic arthritis model group, (C) low-dose D8F2 group (1 mg/kg), (D) medium-dose D8F2 group (3 mg/kg), and (E) high-dose D8F2 group (10 mg/kg). Joint fluid samples were collected at 72 h after surgery, and enzyme-linked immunosorbent assay was performed to measure the following inflammatory factors: tumor necrosis factor α (TNF-α) and interleukin 1β. One week after the surgery, rats were killed, and immunohistochemical staining was applied to detect the matrix metalloproteinase (MMP1 and MMP3) expression in the synovium. In cultured synovial fibroblast experiments, the D8F2-induced ubiquitination of TNF receptor–associated factor 2 (TRAF2) was examined by immunoprecipitation, and nuclear translocation of p65 nuclear factor-κB (p65NF-κB) mediated by TNF-α and D8F2 was analyzed by western blotting. ResultsIn the traumatic arthritis model group, the inflammatory factors and MMPs were significantly increased relative to the sham operation control group (P < 0.05), whereas D8F2 could downregulate these factors in a dose-dependent manner (P < 0.05). The results from in vitro studies indicated that D8F2 can induce TRAF2 ubiquitination and inhibit the nuclear translocation of p65NF-κB mediated by TNF-α. Conclusionsp75 Tumor necrosis factor receptor monoclonal antibody has a therapeutic effect on traumatic arthritis, which may occur via the downregulation of inflammatory factors and MMPs at the transcription level because of TRAF2 degradation and inhibited activation of NF-κB.

Tumor Necrosis Factor in Traumatic Brain Injury: Effects of Genetic Deletion of p55 or p75 Receptor

The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm(3)) was significantly reduced compared with WT (19.7±3.4 mm(3)) and p75 (-/-) mice (20.9±3.2 mm(3)). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.

Murine analogues of etanercept and of F8-IL10 inhibit the progression of collagen-induced arthritis in the mouse

IntroductionEtanercept is a fusion protein consisting of the soluble portion of the p75-tumor necrosis factor receptor (TNFR) and the Fc fragment of human IgG1, which is often used for the treatment of patients with rheumatoid arthritis. F8-IL10 is a human immunocytokine based on the F8 antibody and interleukin-10, which is currently being investigated in rheumatoid arthritis with promising clinical results. We have aimed at expressing murine versions of these two fusion proteins, in order to assess their pharmaceutical performance in the collagen-induced model of rheumatoid arthritis in the mouse.MethodsTwo fusion proteins (termed muTNFR-Fc and F8-muIL10) were cloned, expressed in chinese hamster ovary (CHO) cells, purified and characterized. Biological activity of muTNFR-Fc was assessed by its ability to inhibit TNF-induced killing of mouse fibroblasts, while F8-muIL10 was characterized in terms of muIL10 activity, of binding affinity to the cognate antigen of F8, the alternatively-spliced EDA domain of fibronectin, by quantitative biodistribution analysis and in vivo imaging. The therapeutic activity of both fusion proteins was investigated in a collagen-induced mouse model of arthritis. Mouse plasma was analyzed for anti-drug antibody formation and cytokine levels were determined by bead-based multiplex technology. The association of F8-IL10 proteins with blood cells was studied in a centrifugation assay with radiolabeled protein.ResultsBoth fusion proteins exhibited excellent purity and full biological activity in vitro. In addition, F8-muIL10 was able to localize on newly-formed blood vessels in vivo. When used in a murine model of arthritis, the two proteins inhibited arthritis progression. The activity of muTNFR-Fc was tested alone and in combination with F8-huIL10. The chimeric version of F8-IL10 was not better then the fully human fusion protein and showed similar generation of mouse anti-fusion protein antibodies. Incubation studies of F8-muIL10 and F8-huIL10 with blood revealed that only the fully human fusion protein is not associated with cellular components at concentrations as low as 0.2 μg/ml, thus facilitating its extravasation from blood vessels.ConclusionsThe described products may represent useful research tools for the study of the anti-arthritic properties of TNF blockade and of IL10-based immunocytokines in syngeneic immunocompetent models of arthritis.

A study on inhibition of inflammation via p75TNFR signaling pathway activation in mice with traumatic brain injury

ObjectiveTo investigate the effects of and mechanisms underlying the activation of the p75 tumor necrosis factor receptor (p75TNFR) signaling pathway in inflammatory responses in mice with traumatic brain injury. MethodsWe first generated hybridomas that produced antibodies specific for p75TNFR, by inoculating BALB/c mice with antigenic peptides derived from mouse p75TNFR, which is critical to the binding of tumor necrosis factor-alpha (TNF-α) and p75TNFR. The isotype, epitope, titer, specificity, and affinity constant of monoclonal antibodies (mAbs) were determined using commercial kits and enzyme-linked immunosorbent assay. We then screened the agonist antibody via L929 cytotoxicity assay. The levels of inflammatory factors were detected in C57BL/6 mice with traumatic brain injury and then the mice were injected with either saline (control) or p75TNFR agonist mAb. Furthermore, we investigated the effects of p75TNFR agonist mAb on p38MAPK and nuclear factor-κB signals. ResultsSeven mAbs against p75TNFR were generated. Among them, the mAb D8F2 could markedly enhance the cytotoxicity of TNF-α on L929 cells. In a traumatic brain injury model, D8F2 could inhibit the levels of inflammatory factors and downregulate RNA transcription of these factors by suppressing the activation of p38 mitogen-activated protein kinase and nuclear factor-κB. ConclusionThe mAb D8F2 could inhibit posttraumatic inflammatory responses effectively. In this study, we developed an agonist anti-mouse p75TNFR mAb, which may be used in the future to devise new strategies for the clinical treatment of inflammation after trauma.

Role of T cells in ovariectomy induced bone loss—revisited

Role of T cells in ovariectomy induced bone loss—revisited

Tumor necrosis factor-α-mediated threonine 435 phosphorylation of p65 nuclear factor-κB subunit in endothelial cells induces vasogenic edema and neutrophil infiltration in the rat piriform cortex following status epilepticus.

BackgroundStatus epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-α in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE.MethodsSE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits.ResultsFollowing SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC.ConclusionThese findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.

Transgene-mediated expression of tumor necrosis factor soluble receptor attenuates morphine tolerance in rats

Opiate/narcotic analgesics are the most effective treatments for chronic severe pain, but their clinical utility is often hampered by the development of analgesic tolerance. Recent evidence suggests chronic morphine may activate glial cells to release proinflammatory cytokines. In this study, we used herpes simplex virus (HSV) vectors-based gene transfer to dorsal root ganglion to produce a local release of p55 TNF soluble receptor in the spinal cord in rats with morphine tolerance. Subcutaneous inoculation of HSV vectors expressing p55 TNF soluble receptor into the plantar surface of the hindpaws, enhanced the antinociceptive effect of acute morphine in rats. Subcutaneous inoculation of those vectors into hindpaws also delayed the development of chronic morphine tolerance in rats. TNF soluble receptor expressed by HSV vector reduced gene transcription of mRNA of spinal TNFα and IL-1β induced by repeated morphine. Furthermore, we found that TNF soluble receptor mediated by HSV, reversed the upregulation of TNFα, IL-1β and phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by repeated morphine. These results support the concept that proinflammatory cytokines may play an important role in the pathogenesis induced by morphine. This study provides a novel approach to treating morphine tolerance.

T2 Blockade of intraalveolar p55 TNF-receptor signalling by a domain antibody decreases inflammation and oedema in an in vivo mouse model of ventilator-induced lung injury

<h3>Introduction and Objectives</h3> Tumour necrosis factor (TNF) alpha is transiently up-regulated within the alveolar space during ventilator-induced lung injury (VILI). We previously found that the two TNF receptors play opposing roles during VILI in knock-out mice, with p55 promoting but p75 preventing pulmonary oedema. This suggests that specific blockade of p55 receptor signalling within the alveolar space may be beneficial in VILI. Domain antibodies (dAbs) are the smallest antigen-binding fragments of the IgG molecule, which may have advantages over complete antibodies due to their small size and monovalent binding (mAbs often have agonist activity due to receptor cross-linking). In this study we tested the effects of an intratracheally (i.t.) delivered dAb that binds to and inhibits the murine p55 receptor (Biopharmaceutical R&amp;D, GlaxoSmithKline), on pulmonary oedema and inflammation in mouse models of VILI. <h3>Methods</h3> C57BL6 mice were ventilated with a high-stretch protocol (standardised by plateau pressure at 12.5–13.5 cm H₂O; tidal volume 20–22 ml/kg, PEEP 3 cm H₂O, O₂ with 2–4% CO₂). Mice then received an i.t. bolus of either non-specific ‘dummy’ dAb or p55-specific dAb (25 μg in 50 μl), and were ventilated for up to 4 h (1-hit model). As a 2-hit model, 20 ng LPS were included in the dAb bolus. Development of lung injury was assessed by respiratory elastance and blood gases, and protein level in bronchoalveolar lavage fluid (BALF) at termination. In the 2-hit model, neutrophil infiltration into BALF, the activation state of alveolar macrophages, and neutrophil margination within lung vasculature were all assessed by flow cytometry. <h3>Results</h3> High stretch ventilation produced deteriorations in elastance and PO₂ and high BALF protein in both models. Treatment with the p55-specific dAb substantially attenuated all of these changes in the 1-hit model (Abstract T2 Table 1). In the 2-hit model, p55 blockade prevented deteriorations in elastance and oxygenation, and significantly decreased neutrophil margination, intraalveolar neutrophil infiltration and ICAM-1 expression on alveolar macrophages. <h3>Conclusions</h3> Use of dAbs to selectively inhibit intra-alveolar p55 TNF receptor signalling may open new therapeutic approaches for ventilated patients with acute lung injury. This study was supported by Biopharmaceutical R&amp;D, GlaxoSmithKline.

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPS-associated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade.

Atherosclerosis

Atherosclerosis is a very complex pathology. Over the past two decades we have come to appreciate that a major component of this pathological process is chronic inflammation. This inflammatory state is not only characterized by infiltration of lipid laden macrophages, the hallmark cell of this disease, into the vascular wall, but also is characterized by the infiltration of a host of other inflammatory cells. The complex interaction of inflammatory cells with the normal residents of the vascular wall (ie, endothelial and smooth muscle cells) directs the progression of the disease. Inflammatory cells secrete a variety of chemokines and cytokines which have a profound effect on the development and progression of the plaque. Moreover, many of these cytokines can mediate both pro- and antiatherogenic processes depending on the cellular milieu. The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies encompass numerous cytokines and receptors suggested to play a pivotal role in atherogenesis. Although many members of these families such as TNF-α and CD40 ligand and their putative receptors are considered to be proatherogenic,1–4 studies have also demonstrated an antiatherogenic role for others, including the p55 TNFR.5 TNF-like weak inducer of apoptosis (TWEAK) and its putative receptor, fibroblast growth factor-inducible 14 (Fn14), are also members of the TNF and TNFR superfamilies, respectively. Both TWEAK and Fn14 have been detected in human atherosclerotic plaques, suggesting that these molecules may also play a role in the atherogenic process. Clinical …

Heterogeneity of microglia and TNF signaling as determinants for neuronal death or survival

Microglia do not constitute a single, uniform cell population, but rather comprise cells with varied phenotypes, some which are beneficial and others that may require active regulatory control. Thus, gaining a better understanding of the heterogeneity of resident microglia responses will contribute to any interpretation regarding the impact of any such response in the brain. Microglia are the primary source of the pro-inflammatory cytokine, tumor necrosis factor (TNF) that can initiate various effects through the activation of membrane receptors. The TNF p55 receptor contains a death domain and activation normally leads to cellular apoptosis; however, under specific conditions, receptor activation can also lead to the activation of NF-κB and contribute to cell survival. These divergent outcomes have been linked to receptor localization with receptor internalization leading to cell death and membrane localization supporting cell survival. A second TNF receptor, TNF p75 receptor, is normally linked to cell growth and survival, however, it can cooperate with the p55 receptor and contribute to cell death. Thus, while an elevation in TNFα in the brain is often considered an indicator of microglia activation and neuroinflammation, a number of factors come into play to determine the final outcome. Data are reviewed demonstrating that heterogeneity in morphological response of microglia and the expression of TNFα and TNF receptors are critical in identifying and characterizing neurotoxic events as they relate to neuroinflammation, neuronal damage and in stimulating neuroprotection.

The influence of type 1 diabetes mellitus on spermatogenic gene expression

Routine semen analysis found no differences in diabetic men; however, mRNA profiles showed changes in the expression of genes involved in oxidative stress.

Absence of p55 TNF Receptor Reduces Atherosclerosis, but Has No Major Effect on Angiotensin II Induced Aneurysms in LDL Receptor Deficient Mice

BackgroundThe aim of the current study was to investigate the role of p55 TNF Receptor (p55 TNFR), the main signaling receptor for the pro-inflammatory cytokine tumor necrosis factor (TNF), in the development of two vascular disorders: atherosclerosis and angiotensin (Ang) II-induced abdominal aortic aneurysms (AAA).Methodology/Principal Findingsp55 TNFR deficient mice were crossed to an LDL receptor deficient background and were induced for the development of either atherosclerosis or AngII-induced AAA, and compared to littermate controls, wild-type for p55 TNFR expression. p55 TNFR deficient mice developed 43% smaller atherosclerotic lesions in the aortic sinuses compared to controls. Moreover, expression of CD68, a macrophage specific marker, exhibited a 50% reduction in the aortic arches. Decreased atherosclerosis correlated with a strong down-regulation in the expression of adhesion molecules, such as VCAM-1 and ICAM-1, by p55 TNFR deficient endothelium. In addition, expression levels of the pro-inflammatory cytokines and chemokines TNF, IL-6, MCP-1 and RANTES were significantly reduced in aortas of p55 TNFR deficient mice. In contrast, in the AngII-induced model of AAA, p55 TNFR deficiency correlated with a slight trend towards increased aneurismal lethality, but the incidence of aortic rupture due to a dissecting aneurysm, and the expansion of the suprarenal aorta were not significantly different compared to controls.Conclusion/SignificanceWe found that p55 TNFR expression promotes atherosclerosis, among other mechanisms, by enhancing expression of endothelial adhesion molecules, while it seems to have no major role in the development of AngII-induced AAA.

Leukemic Phase of Follicular Lymphoma after Treatment with Etanercept in a Patient with Psoriasis

Etanercept, a fully human soluble recombinant p75 tumor necrosis factor (TNF) receptor that blocks the binding of TNF to cell surface receptors, is approved for the treatment of psoriatic arthritis and other rheumatic conditions in the US and Europe. Ever since the introduction of anti-TNF treatment in patients with inflammatory autoimmune diseases, there have been concerns about a possible tumor-promoting effect of such a measure. We report a rare case of leukemic phase of follicular lymphoma in a 62-year-old man with moderate-to-severe plaque psoriasis receiving long-term treatment with etanercept for 3 years. Although the association is intriguing, no causal relationship is suggested.

Tumor necrosis factor receptor–associated periodic syndrome: Toward a molecular understanding of the systemic autoinflammatory diseases

Almost a decade has elapsed since the concept of autoinflammation was advanced to describe conditions characterized by ostensibly unprovoked inflammation, without the hightiter autoantibodies or antigen-specific T-cells found in known autoimmune diseases. This concept was introduced following the identification of mutations in the p55 tumor necrosis factor receptor (TNFR1) in patients with a dominantly inherited syndrome of systemic inflammation (TRAPS) (1). Systemic autoinflammatory diseases are caused by aberrant activation of the innate immune system. Some result in recurrent episodes of fever, localized serositis and skin rashes. Two hereditary recurrent fevers, familial Mediterranean fever (FMF) and the TNF receptor-associated periodic syndrome (TRAPS) were prototypes for this diagnostic category. In the past 10 years this concept has been extended to include a number of Mendelian disorders, including other hereditary recurrent fevers, as well as more common diseases with complex modes of inheritance including Behcet's disease and Crohn's disease (2). When the molecular basis of TRAPS was discovered it was considered an exceedingly rare disease with only a few families described in the literature. Over the past decade, more than 50 disease-associated mutations have been identified in hundreds of patients from a variety of ethnic backgrounds (3). Genotype-phenotype studies showed that mutations at cysteine residues are associated with a more severe phenotype and higher incidence of amyloidosis (4). Although, most TRAPS-associated mutations are fully penetrant, two TNFR1 variants, P46L and R92Q, have been also identified in asymptomatic family members, and at a low frequency in healthy populations. Tumor necrosis factor (TNF) is a pleiotropic cytokine that mediates a wide range of cellular activities primarily through its interaction with TNF receptor 1 (TNFR1; TNFRSF1A; CD120a; p55/p60). Triggering the TNF signaling cascade results in an array of responses, including apoptosis, inflammation and modulation of the immune response. TNFR1 is constitutively expressed on the cell surface in most tissues. It is a large polypeptide with an extracellular domain, consisting of 4 cysteine-rich domains (CRD), a transmembrane domain, and an intracellular death domain (DD). Each CRD includes 3 pairs of cysteine residues that form intramolecular disulfide bonds important in maintaining the 3dimensional conformation of the extracellular part of the receptor. Thus, a substitution at a cysteine residue has the potential to disrupt the relevant disulfide bond and result in significant structural perturbation. The first CRD, sometimes called the pre-ligand association domain (PLAD), allows for TNF-independent interactions of TNFR1 molecules,