Excess Tumor Necrosis Factor Research Articles

TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Ileal inflammation is reduced due to treatment with a metalloprotease from BmooMP-α-I snake venom in an experimental model of Toxoplasma gondii infection.

The selection process for advanced therapies in patients with inflammatory bowel diseases (IBDs) must prioritize safety, especially when considering new biologic agents or oral molecule modulators. In C57BL/6 mice, oral infection with Toxoplasma gondii induces intestinal inflammation through excessive tumor necrosis factor (TNF) production, making TNF neutralization a potential therapeutic intervention. Considering this, the present study aimed to evaluate the therapeutic effects of BmooMP-α-I, a snake venom metalloprotease isolated from Bothrops moojeni, which could promote TNF hydrolysis, in treating T. gondii-induced ileitis. The results showed that C57BL/6 mice orally infected with 50 cysts of T. gondii from the Me49 strain and treated with BmooMP-α-I exhibited prolonged survival and improved morbidity scores. Additionally, the treatment ameliorated both the macroscopic and microscopic aspects of the intestine, reduced macrophage influx, and decreased the production of inflammatory mediators by mesenteric lymph node cells. These findings provide compelling experimental evidence supporting the ability of BmooMP-α-I to alleviate ileal inflammation. Considering that the currently available therapeutic protocols are not completely effective and often result in side effects, the exploration of alternative strategies involving novel therapeutic agents, as demonstrated in this study, has the potential to significantly enhance the quality of life for patients suffering from inflammatory bowel diseases.

A Translational Approach to Identifying and Targeting TNF Signaling in Idiopathic Multicentric Castleman Disease

Idiopathic multicentric Castleman disease (iMCD) is a rare, immunological illness with an unknown etiology. It is characterized by multiple enlarged lymph nodes with unique histopathological features and systemic inflammation resulting from cytokine release syndrome, which can rapidly develop into multiple organ failure and death. Inhibition of the pro-inflammatory cytokine interleukin-6 (IL-6) with siltuximab, the only FDA-approved therapy for iMCD, is an effective treatment for approximately one-half of patients. Patients who do not respond to IL-6 inhibition have few treatment options beyond cytotoxic chemotherapy. A better understanding of the pathogenic mechanisms underlying iMCD is critically needed to uncover new potential treatments for patients. To characterize the immune dysregulation in iMCD, our lab previously profiled serum analytes and circulating cell types in patient blood during active disease. Serum proteomic analyses identified tumor necrosis factor (TNF) signaling as a highly enriched pathway in both siltuximab responders and non-responders. Both immunophenotypic and serum proteomic data indicated that T cells, which can produce TNF, were activated in iMCD. However, whether TNF production by activated T cells was a key mechanism promoting iMCD was unclear. To determine if T cells contribute to the characteristic cytokine storm in iMCD, we investigated the ability of T cells from iMCD patients to produce different inflammatory cytokines including TNF. Upon stimulation with phorbol myristate acetate and ionomycin (PMA/I), both naïve and non-naïve CD4 + T cells from iMCD patients (n=9) produced significantly more TNF compared to healthy controls (n=9). There was a >2-fold increase in the frequency of TNF-expressing naïve CD4 + T cells from iMCD patients versus healthy controls. We also found a significant, yet marginal, increase in the frequency of TNF + non-naïve CD4 + T cells from iMCD patients. Although TNF and IFN-γ are both well-established markers of T cell activation, we did not observe a similar rise in interferon-gamma (IFN-γ) after stimulation in either CD4 + T cell subset. Taken together, these data indicate that CD4 + T cells in iMCD patients hyper-respond to stimulation specifically by producing excess TNF. In parallel to flow cytometric, proteomic, and T cell stimulation data, we leveraged KGML-xDTD, a knowledge graph-based machine learning framework, to predict potential novel drug treatments for iMCD. Utilizing 3,659,165 nodes and 18,291,237 edges in RTX-KG2 from 70 public biomedical sources, we trained a random forest-based machine learning algorithm on true positive and true negative treatment relationships. The top three novel predicted treatments for iMCD included two TNF inhibitors, adalimumab and certolizumab pegol, and the B cell depleting agent, rituximab, the second most prescribed drug for iMCD after siltuximab. We then used the reinforcement learning module of KGML-xDTD to predict the mechanism linking adalimumab to iMCD, which included IL-4, IL-6, IL-8, IL-10, STAT3, and CD4. These data reveal a potential new treatment strategy and further implicate TNF by CD4-expressing T cells in iMCD pathogenesis. In addition to our laboratory findings and predictive modeling data that suggest that TNF production by T cells promotes iMCD, we report the successful treatment of a highly refractory iMCD patient with off-label use of a TNF blocker. When a 50-year old iMCD patient was experiencing multi-organ system dysfunction and preparing for hospice care after not responding to IL-6 inhibition, IL-1 inhibition, Bruton's tyrosine kinase (BTK) inhibition, chemotherapy, and autologous stem cell transplantation, we initiated treatment with adalimumab alongside BTK inhibition. Within 3 days of the first infusion, the patient's symptoms and organ dysfunction began to improve and the patient has been in remission for over 6 months. We utilized a translational research approach including experimental and unbiased machine learning approaches to identify TNF as a novel therapeutic target that we inhibited to treat a highly refractory iMCD patient. Together, our data suggest that over-production of TNF, in part by activated T cells, promotes iMCD pathogenesis and highlight that further research is needed into TNF inhibition as a potential treatment strategy for iMCD.

Rapid improvement in severe long COVID following perispinal etanercept

Background This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. Methods Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 m Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25 mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration. Results Following perispinal etanercept administration there was immediate neurological improvement. At 24 h, there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measurable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved. Conclusion Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport.

Tumor necrosis factor (TNF) is a critical host resistance factor against tuberculosis. However, excess TNF produces susceptibility by increasing mitochondrial reactive oxygen species (mROS), which initiate a signaling cascade to cause pathogenic necrosis of mycobacterium-infected macrophages. Here, using the zebrafish, we identify the mechanism of TNF-induced mROS in tuberculosis. Excess TNF in mycobacterium-infected macrophages elevates mROS production by reverse electron transport (RET) through complex I. TNF-activated cellular glutamine uptake increases the Krebs cycle intermediate succinate. Oxidation of this elevated succinate by complex II drives RET, thereby generating the mROS superoxide at complex I. The complex I inhibitor, metformin, a widely used anti-diabetic drug, prevents TNF-induced mROS and necrosis of Mycobacterium tuberculosis-infected zebrafish and human macrophages, suggesting its utility in tuberculosis therapy.

NF–κB–mediated TET2–dependent TNF promoter demethylation drives Mtb–upregulation TNF expression in macrophages

Tumor necrosis factor (TNF) is essential for the host defense against tuberculosis (TB). However, scarcity or excessive TNF production in macrophages can also increase susceptibility to TB. The precise mechanisms underlying how Mycobacterium tuberculosis (Mtb) induces TNF over-expression are unclear. Here, we show that Mtb infection significantly increases 5-hydroxylmethylocytosine (5hmC) levels in the TNF promoter. Luciferase reporter assays identify the precise methylated CpG sites that are essential to regulating TNF promoter activity. Infection simultaneously promotes the expression of the TET2 demethylase in macrophages. After inhibiting NF-κB or knocking down TET2, we found that TNF promoter demethylation levels is increased while Mtb-induced TNF expression decrease. Here, NF-κB binds to TET2 and mediates its recruitment to the TNF promoter to induce TNF demethylation. Finally, we show that TLR2 activation during Mtb infection promotes NF-κB translocation into the nucleus which is important for NF-κB-mediated TET2-dependent TNF promoter demethylation thus helps drive Mtb-induced TNF expression. Targeting this axis might be a novel strategy for host-directed therapy against TB.

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches.

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

Generalized Shwartzman Reaction as an Experimental Endotoxin Shock Model: Role of Intermediate T Cell Receptor-Expressing Innate T Lymphocytes in its Pathogenesis

Endotoxin and its induced exaggerative responses of proinflammatory cytokines such as Tumor Necrosis Factor (TNF) cause human septic shock. The generalized Shwartzman reaction is considered as an experimental endotoxin shock model and its representative features are high lethality and hypersensitive inflammatory response to endotoxin, in particular excessive TNF production. The generalized Shwartzman reaction can be induced by Interleukin (IL)-12 priming and subsequent endotoxin challenge. IL-12 primes the intermediate T cell receptor (TCR)-expressing innate T lymphocytes (natural killer T cells and CD8+CD122+ T cells in mice, CD56+ T cells and CD57+ T cells in human) to produce IFN-γ, which in turn preconditions macrophages to produce a large amount of TNF in response to endotoxin. These intermediate TCR innate T lymphocytes play a pivotal role for the occurrence of this generalized Shwartzman reaction. Some of the intermediate TCR-expressing innate T lymphocytes (CD8+CD122+ T cells in mice and CD57+ T cells in human), which are considered as extrathymically developed T lymphocytes, are increased with age and closely involved in age-dependent augmentation of murine generalized Shwartzman reaction and human Shwartzman-like reaction, which may reflect an exacerbation of septic shock in elderly. However, these intermediate TCR innate T lymphocytes normally augment host immunity against malignant tumors and refractory bacterial infections, which are critical threats in aged hosts. Thus, intermediate TCR-expressing innate T lymphocytes may be a double-edged sword on the host defense, especially elderly hosts.

TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis through a Mitochondrial-Lysosomal-Endoplasmic Reticulum Circuit.

SummaryNecrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.

Protective effect of resveratrol against hepatic damage induced by heat stress in a rat model is associated with the regulation of oxidative stress and inflammation.

Heat stress jeopardizes humans and animals health, and results in enormous economic loss in public health care and livestock production. The aim of this study was to investigate the effects of resveratrol on hepatic oxidative stress and inflammation in heat-stressed rats. Male Sprague-Dawley rats were orally fed with 100 mg resveratrol/kg body weight/day prior to heat stress (40 ∘C per day for 1.5 h) exposure for 3 consecutive days. Serum and liver samples were collected for the analysis of hepatic injury, redox status and immune response. The results showed that the heat-stress-induced increased aspartate aminotransferase activities in the serum, aberrant hepatic histology, excessive hepatic malondialdehyde and tumor necrosis factor alpha concentrations, and up-regulation of heat shock protein 70, superoxide dismutase 1, glutathione peroxidase 1, toll-like receptor 4 and interleukin 10 mRNA expression in the liver were mitigated by oral resveratrol treatment. Collectively, the beneficial effects of resveratrol on hepatic damage induced by heat stress were associated with the regulation of oxidative stress and inflammation.

A Knock-In Tristetraprolin (TTP) Zinc Finger Point Mutation in Mice: Comparison with Complete TTP Deficiency.

Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that can bind to AU-rich element-containing mRNAs and promote their decay. TTP knockout mice develop a severe inflammatory syndrome, largely due to excess tumor necrosis factor (TNF), whose mRNA is a direct target of TTP binding and destabilization. TTP's RNA binding activity and its ability to promote mRNA decay are lost when one of the zinc-coordinating residues of either zinc finger is mutated. To address several long-standing questions about TTP activity in intact animals, we developed a knock-in mouse with a cysteine-to-arginine mutation within the first zinc finger. Homozygous knock-in mice developed a severe inflammatory syndrome that was essentially identical to that of complete TTP deficiency, suggesting that TTP's critical anti-inflammatory role in mammalian physiology is secondary to its ability to bind RNA. In addition, there was no evidence for a "dominant-negative" effect of the mutant allele in heterozygotes, as suggested by previous experiments. Finally, mRNA decay experiments in mutant macrophages demonstrated that TTP can regulate the stability of its own mRNA, albeit to a minor extent. These studies suggest that RNA binding is an essential first step in the physiological activities of members of this protein family.

Excess Blood Flow Response to Acute Resistance Exercise in Individuals Who are Obese or Nonobese.

Lipford, GF, Evans, RK, Acevedo, EO, Wolfe, LG, and Franco, RL. Excess blood flow response to acute resistance exercise in individuals who are obese or nonobese. J Strength Cond Res 31(11): 3120-3127, 2017-Resistance exercise (RE) is a commonly recommended treatment option for obese individuals. However, little is known regarding alterations in vasodilatory responses to RE, which could impair exercise tolerance. No studies to date have compared microvascular vasodilatory capacity, assessed by excess blood flow (EBF), responses in individuals who are obese or nonobese following acute RE. The purpose of the study was to evaluate EBF before and up to 24-hour after a single RE bout in obese (n = 18, 38.1 ± 7.64% body fat) and nonobese (n = 10, 23.6 ± 4.03% body fat) individuals who volunteered to participate. Each subject completed a leg flexion and knee extension one repetition maximum (1RM) test, and subsequently completed 4 sets of 8 repetitions at 85% of 1RM. Excess blood flow, adiponectin, and tumor necrosis factor α (TNF-α) were evaluated at baseline (PRE-RE), immediately after (POST-RE), and 1 (POST-1) and 24 (POST-24) hours after exercise. A repeated-measures analysis of variance revealed a significant interaction for EBF between the 2 groups (p = 0.029). The estimated marginal means plot suggested that obese individuals had a significant increase in POST-RE EBF in comparison with PRE-RE EBF (428.54 ± 261.59 vs. 547.00 ± 311.15 ml/100 ml/min·s; p = 0.046). In addition, EBF significantly decreased at POST-24 in comparison with POST-RE in the obese individuals (547.00 ± 311.15 vs. 389.33 ± 252.32 ml/100 ml/min·s; p = 0.011). Changes in EBF were not related to adiponectin or TNF-α. An acute bout of RE resulted in an opposite EBF response between nonobese and obese individuals immediately after RE. Furthermore, only the obese individuals displayed a significant increase in EBF immediately after RE, which was significantly reduced 24 hours after the RE bout. Microvascular vasodilatory capacity may alter the adaptive exercise response associated with RE, requiring alterations to frequency, intensity, and/or duration that are specific to populations of various body composition profiles.

Response by Steinberg et al to Letter Regarding Article, “Clinical Outcomes of Transplanted Modified Bone Marrow–Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2A Study”

We thank Dr Clark for his comments. Immunomodulation related to protein and molecular factors secreted by the SB623 cells could be one of the mechanisms underlying the observed neurological recovery in our patients1 and could suggest that there is ongoing chronic inflammation >6 months after stroke that is suppressing intact neural circuits and rendering them nonfunctional. This concept has some support in the recent preclinical and clinical literature.2 In addition, it is conceivable that the transplanted SB623-secreted factors are enhancing native neurogenesis or synaptogenesis, potentially through blocking excess tumor necrosis factor effects after stroke, although this is unproven. It will be important …

Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents.

The basic mechanism of the major neurodegenerative diseases, including neurogenic pain, needs to be agreed upon before rational treatments can be determined, but this knowledge is still in a state of flux. Most have agreed for decades that these disease states, both infectious and non-infectious, share arguments incriminating excitotoxicity induced by excessive extracellular cerebral glutamate. Excess cerebral levels of tumor necrosis factor (TNF) are also documented in the same group of disease states. However, no agreement exists on overarching mechanism for the harmful effects of excess TNF, nor, indeed how extracellular cerebral glutamate reaches toxic levels in these conditions. Here, we link the two, collecting and arguing the evidence that, across the range of neurodegenerative diseases, excessive TNF harms the central nervous system largely through causing extracellular glutamate to accumulate to levels high enough to inhibit synaptic activity or kill neurons and therefore their associated synapses as well. TNF can be predicted from the broader literature to cause this glutamate accumulation not only by increasing glutamate production by enhancing glutaminase, but in addition simultaneously reducing glutamate clearance by inhibiting re-uptake proteins. We also discuss the effects of a TNF receptor biological fusion protein (etanercept) and the indirect anti-TNF agents dithio-thalidomides, nilotinab, and cannabinoids on these neurological conditions. The therapeutic effects of 6-diazo-5-oxo-norleucine, ceptriaxone, and riluzole, agents unrelated to TNF but which either inhibit glutaminase or enhance re-uptake proteins, but do not do both, as would anti-TNF agents, are also discussed in this context. By pointing to excess extracellular glutamate as the target, these arguments greatly strengthen the case, put now for many years, to test appropriately delivered ant-TNF agents to treat neurodegenerative diseases in randomly controlled trials.

Adiponectin Enhances Antibacterial Activity of Hematopoietic Cells by Suppressing Bone Marrow Inflammation

Obesity has been shown to increase the morbidity ofinfections, however, the underlying mechanisms remain largely unknown. Here we demonstrate thatobesity caused adiponectin deficiency in the bone marrow (BM), which led to an inflamed BM characterized by increased tumor necrosis factor (TNF) production from bone marrow macrophages. Hematopoietic stem and progenitor cells (HSPCs) chronically exposed to excessive TNF in obese marrow aberrantly expressed cytokine signaling suppressor SOCS3, impairing JAK-STAT mediated signal transduction and cytokine-driven cell proliferation. Accordingly, both obese and adiponectin-deficient mice showed attenuated clearance of infected Listeria monocytogenes, indicating that obesity or loss of adiponectin is critical for exacerbation of infection. Adiponectin treatment restored the defective HSPC proliferation and bacterial clearance of obese and adiponectin-deficient mice, affirming the importance of adiponectin against infection. Taken together, our findings demonstrate that obesity impairs hematopoietic response against infections through a TNF-SOCS3-STAT3 axis, highlighting adiponectin as a legitimate target against obesity-related infections.

Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome.

Tristetraprolin (TTP) acts by binding to AU-rich elements in certain mRNAs, such as tumor necrosis factor (TNF) mRNA, and increasing their decay rates. TTP knockout mice exhibit a profound inflammatory syndrome that is largely due to increased TNF levels. Although TTP's effects on gene expression have been well studied in cultured cells, little is known about its functions in intact tissues. We performed deep RNA sequencing on spleens from TTP knockout mice that were also deficient in both TNF receptors ("triple knockout" mice) to remove the secondary effects of excess TNF activity. To help identify posttranscriptionally regulated transcripts, we also compared changes in mature mRNA levels to levels of transiently expressed pre-mRNA. In the triple knockout spleens, levels of 3,014 transcripts were significantly affected by 1.5-fold or more, but only a small fraction exhibited differential mRNA/pre-mRNA changes suggestive of increased mRNA stability. Transferrin receptor mRNA, which contains two highly conserved potential TTP binding sites, was significantly upregulated relative to its pre-mRNA. This was reflected in increased transferrin receptor expression and increased splenic iron/hemosiderin deposition. Our results suggest that TTP deficiency has profound effects on the splenic transcriptome, even in the absence of secondary increases in TNF activity.

A Neurologist's Guide to TNF Biology and to the Principles behind the Therapeutic Removal of Excess TNF in Disease.

Tumor necrosis factor (TNF) is an ancient and widespread cytokine required in small amounts for much physiological function. Higher concentrations are central to innate immunity, but if unchecked this cytokine orchestrates much chronic and acute disease, both infectious and noninfectious. While being a major proinflammatory cytokine, it also controls homeostasis and plasticity in physiological circumstances. For the last decade or so these principles have been shown to apply to the central nervous system as well as the rest of the body. Nevertheless, whereas this approach has been a major success in treating noncerebral disease, its investigation and potential widespread adoption in chronic neurological conditions has inexplicably stalled since the first open trial almost a decade ago. While neuroscience is closely involved with this approach, clinical neurology appears to be reticent in engaging with what it offers patients. Unfortunately, the basic biology of TNF and its relevance to disease is largely outside the traditions of neurology. The purpose of this review is to facilitate lowering communication barriers between the traditional anatomically based medical specialties through recognition of shared disease mechanisms and thus advance the prospects of a large group of patients with neurodegenerative conditions for whom at present little can be done.

Redeeming an old foe: protective as well as pathophysiological roles for tumor necrosis factor in inflammatory bowel disease.

Tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2 are major therapeutic targets for inflammatory bowel disease. Research advances have demonstrated that TNF produces pleiotropic responses in the gastrointestinal (GI) tract. Although in excess TNF can contribute to GI pathology, TNF is also a critical protective factor to promote GI homeostasis following injury and inflammation. Genetic studies using candidate and genome-wide association study approaches have identified variants in TNF or its receptors that are associated with Crohn's disease or ulcerative colitis in multiple populations, although the basis for these associations remains unclear. This review considers the efficacy and mechanism of anti-TNF therapies for inflammatory bowel disease to reconcile the many disparate aspects of TNF research and to consider the potential protective effects of TNF signaling in GI health.

Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimers Disease

Excess tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Alzheimer's disease(AD). Clinical improvement following perispinal administration of etanercept in patients with Alzheimer's disease and other forms of dementia and brain dysfunction is characteristically evident within minutes. The rapidity and constellation of the clinical effects across multiple domains (cognition, mood, memory, motor function, and attention) suggest they are mediated by non-synaptic signaling mechanisms previously unrecognized for etanercept. These mechanisms likely extend beyond the known roles of TNF as a gliotransmitter that modulates synaptic strength, synaptic scaling, and AMPA receptor trafficking. Preliminary basic science and clinical investigation suggests that perispinal administration of etanercept may lead to its rapid penetration into the cerebrospinal fluid (CSF) within the cerebral ventricles. Diffusion of large molecules into the periventricular brain parenchyma is known to occur, but this process may not be sufficient to explain the rapidity of the clinical effects. There exist populations of cells, including CSF-contacting neurons and modified ependymal cells called tanycytes, that have receptive surfaces in direct contact with the CSF. It is hypothesized that the rapid clinical effects of perispinal etanercept involve non-synaptic signal transduction across the ependymal barrier and into neuronal networks via these CSF-contacting cells. This hypothesis challenges the dogma that penetration of a therapeutic into the cerebral parenchyma through the endothelium of the cerebral vasculature (the so-called blood- brain barrier) is necessary to produce rapid clinical effects in AD. CSF-contacting cells may constitute a therapeutic target for a diverse group of brain, psychiatric and spinal disorders.

Biologics targeted at TNF: design, production and challenges

Several biotech-derived drugs aimed at Tumor Necrosis Factor (TNF) have been licensed in the last years, profoundly changing the therapy of several autoimmune diseases based on inflammation, affecting the life of patients and bringing to the market attention the growth potentials of biologics directed at cytokines. The proof of principles that led to the design of these compounds dates back from the nineties, when the involvement of TNF in rheumatoid arthritis was proved by the ability of specific anti-TNF proteins to modulate the inflammatory response in animal models. Monoclonal antibodies aimed at neutralizing the excess TNF were developed with therapeutic purposes, and a chimeric and a full human antibody are now approved for several clinical indications. The design of soluble receptors able to bind and neutralize human TNF paralleled the development of antibodies as therapeutics, and the clinical success of these drugs was achieved by the clever design of a novel recombinant dimeric protein, consisting of the extracellular portion of human TNF receptor linked to the constant portion of a human immunoglobulin. All approved biologics designed to bind and neutralize TNF were obtained through the power of biotechnological methods: the development of these important biopharmaceutical products, their means of production and the challenges they face will be analyzed here in details.