Increased Serum Levels Of TNF-α Research Articles

Modulation of nitrergic pathway by sesamol prevents cognitive deficits and associated biochemical alterations in intracerebroventricular streptozotocin administered rats

Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline and widespread loss of neurons and their synapses in the cerebral cortex and hippocampus. Increasing evidence indicates that factors such as oxidative–nitrergic stress, glutathione depletion, impaired protein metabolism and cholinergic deficit can interact in a vicious cycle, which is central to Alzheimer's disease pathogenesis. Intracerebroventricular (i.c.v.) streptozotocin induced-cognitive impairment has been widely used as an experimental paradigm to study Alzheimer's disease. In the present study, i.c.v. streptozotocin produced significant cognitive deficits as measured in Morris water maze and elevated plus maze task coupled with increased serum TNF-α levels and marked rise in brain acetylcholinesterase and oxidative–nitrergic stress in female Wistar rats. Sesamol (5-hydroxy-1,3-benzodioxole or 3,4-methylenedioxyphenol), a potent anti-oxidant and anti-inflammatory molecule markedly improved cognitive impairment, reduced acetylcholinesterase activity, TNF-α levels and attenuated oxidative–nitrergic stress in brain of i.c.v.-streptozotocin treated rats. Administration of l-arginine (125 mg/kg i.p), a nitric oxide donor, alone to i.c.v.-streptozotocin treated rats accentuated behavioral and biochemical deficits and also abolished the protective effect of sesamol (8 mg/kg). l-NAME (10 mg/kg i.p.), a non-specific NOS inhibitor significantly restored all the behavioral and biochemical indices in i.c.v.-streptozotocin rats. Moreover, combination of l-NAME with sub-effective dose of sesamol (4 mg/kg) potentiated its protective effect. Our findings demonstrate the effectiveness of sesamol in preventing intracerebroventricular streptozotocin-induced cognitive deficits by modulating nitrergic signaling and oxido-inflammatory cascade.

Serum TNF-α levels reflect the clinical severity of envenomation following a Hemiscorpius lepturus sting

Hemiscorpius lepturus (H. lepturus), found in south-western areas of Iran and south of Iraq, is considered to be the most dangerous scorpion in the region, and poses a significant risk to the health of the indigenous population due to the unique, clinical manifestations associated with its sting.. In the present study, 36 patients from the Khuzestan province in the southwest of Iran, displaying varying degrees of envenomation following an H. lepturus scorpion sting, were admitted to hospital. Serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-α (TNF-α) were measured using double-ligand, enzyme-linked, immunosorbent assay (ELISA) kits, and were compared with 30 healthy controls and ten age-matched patients stung by the Mesobuthus eupeus (M. eupeus) scorpion, a less dangerous species that produces primarily neurotoxic manifestations. Blood samples from M. eupeus and H. lepturus victims were taken on admission, and from H. lepturus-stung patients six hours after serotherapy with multivalent anti-venom. When compared to healthy volunteers, with the exception of TNF-α, significantly higher serum cytokine levels were measured in patients following M. eupeus envenomation. However, all three groups of H. lepturus-stung patients showed significantly, and in a severity-related manner, higher mean values for all the interleukins that were measured, including TNF-α, when compared with M. eupeus-stung cases. Six hours after serotherapy, there was a greater reduction in cytokine and TNF-α levels in patients classed as having mild symptoms, in comparison with patients classed as having moderate to severe symptoms. The results of the present study suggest that, unlike M. eupeus, the toxic manifestations observed following being stung by H. lepturus are associated with increased serum TNF-α levels and correlate positively with the clinical severity of the symptoms. Furthermore, serotherapy is only effective when administered to mild cases of H. lepturus scorpion envenomation.

Normobaric hyperoxia induces ischemic tolerance and upregulation of glutamate transporters in the rat brain and serum TNF-α level

Recent studies suggest that intermittent and prolonged normobaric hyperoxia (HO) results in ischemic tolerance to reduce ischemic brain injury. In this research, we attempted to see changes in excitatory amino acid transporters (EAATs) and TNF-α levels following prolonged and intermittent hyperoxia preconditioning. Rats were divided into four experimental groups, each of 21 animals. The first two were exposed to 95% inspired HO for 4 h/day for 6 consecutive days (intermittent HO, InHO) or for 24 continuous hours (prolonged HO, PrHO). The second two groups acted as controls, and were exposed to 21% oxygen in the same chamber. Each main group was subdivided to middle cerebral artery occlusion (MCAO-operated), sham-operated (without MCAO), and intact (without any surgery) subgroups. After 24 h from pretreatment, MCAO-operated subgroups were subjected to 60 min of right MCAO. After 24 h reperfusion, neurologic deficit score (NDS) and infarct volume were measured in MCAO-operated subgroups. EAATs expression and serum TNF-α levels were assessed in sham-operated and intact subgroups. Preconditioning with prolonged and intermittent HO decreased NDS and upregulated EAAT1, EAAT2, and EAAT3 and increased serum TNF-α levels significantly. Although further studies are needed to clarify the mechanisms of ischemic tolerance, the intermittent and prolonged HO seems to partly exert their effects via increase serum TNF-α levels and upregulation of EAATs.

Aggravation of Galactosamine Hepatotoxicity by Albumin in Rats

The effect of rat albumin (RALB) on D-galactosamine (GalN) hepatotoxicity was investigated in male Crl:CD(SD) rats aged 6 weeks. The animals were divided into control, RALB, GalN, and RALB + GalN groups. GalN (800 mg/kg) was intraperitoneally administered immediately after an intravenous injection of RALB (100 mg/kg). The animals were euthanized 6 or 24 h later and subjected to laboratory investigations and histological examinations of the liver. Furthermore, in order to determine the contributing factors of the effect on the hepatotoxicity, intra- and inter-group comparisons were made between liver-injured and normal animals for parameters showing marked fluctuations at 6 h post-dosing. As a result, RALB induced fluctuations in many parameters, but no histological changes were observed in the liver at both 6 and 24 h. GalN induced mild or moderate hepatocyte necrosis (necrosis and/or apoptosis of hepatocytes) at 6 and 24 h, respectively, accompanied by increases in the serum ALT and AST levels. Concurrent administration of RALB with GalN markedly aggravated the GalN-induced hepatotoxicity, as shown by severe hepatocyte necrosis accompanied by further increases in the serum ALT, AST, and T-BIL levels in the surviving animals at 6 and 24 h, and by very severe hepatocyte necrosis with congestion in the dead animals. Moreover, serum tumor necrosis factor-α (TNF- α) level was also increased at 6 h in the RALB + GalN group, but not in the RALB or GalN alone groups. In conclusion, RALB was shown to aggravate GalN hepatotoxicity in rats, and the increased serum TNF-α level is considered to be a contributing factor of the aggravation.

Immune Activation in Patients With Irritable Bowel Syndrome

We set out to test the hypothesis that irritable bowel syndrome (IBS) is characterized by an augmented cellular immune response with enhanced production of proinflammatory cytokines. We further aimed to explore whether symptoms and psychiatric comorbidity in IBS are linked to the release of proinflammatory cytokines. We characterized basal and Escherichia coli lipopolysaccharide (LPS)-induced cytokine production in peripheral blood mononuclear cells (PBMCs) from 55 IBS patients (18 mixed-, 17 constipation-, 20 diarrhea-predominant) and 36 healthy controls (HCs). PBMCs were isolated by density gradient centrifugation and cultured for 24 hours with or without (1 ng/mL) LPS. Cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and IL-6) was measured by enzyme-linked immunosorbent assay. Abdominal symptoms and psychiatric comorbidities were assessed by using the validated Bowel Disease Questionnaire and the Hospital Anxiety and Depression Scale. IBS patients showed significantly (P < .017) higher baseline TNF-alpha, IL-1beta, IL-6, and LPS-induced IL-6 levels compared with HCs. Analyzing IBS subgroups, all cytokine levels were significantly (P < .05) higher in diarrhea-predominant IBS (D-IBS) patients, whereas constipation-predominant IBS patients showed increased LPS-induced IL-1beta levels compared with HCs. Baseline TNF-alpha and LPS-induced TNF-alpha and IL-6 levels were significantly higher in patients reporting more than 3 bowel movements per day, urgency, watery stools, and pain associated with diarrhea compared with patients without these symptoms (all P < .05). LPS-induced TNF-alpha production was associated significantly (r = 0.59, P < .001) with anxiety in patients with IBS. Patients with D-IBS display enhanced proinflammatory cytokine release, and this may be associated with symptoms and anxiety.

Etanercept treatment of cutaneous granulomas in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia, poor antibody responses, and recurrent bacterial infections, usually of the sinorespiratory tract. A not uncommon complication is granuloma of the lungs, spleen, liver, and/or skin. We report the case of an 18-year-old boy with CVID and chronic granulomas of the left arm (since 13 years of age) refractory to treatment with antibiotics, intravenous immunoglobulin, antifungal agents, systemic and intralesional steroids, IFN-gamma, cyclosporine, methotrexate, hydroxychloroquine, localized radiation therapy, and surgical excision. The lesions improved after treatment with the systemic administration of the TNF-alpha inhibitor etanercept for 1 year. Etanercept prevents soluble TNF from binding to its cell membrane receptor, leading to inhibition of its inflammatory cascade. We recommend further trials of etanercept in patients with CVID with noninfectious recalcitrant granulomas.

Chronic Tumor Necrosis Factor-α Inhibition Enhances NO Modulation of Vascular Function in Estrogen-Deficient Rats

Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of vascular disease. Clinical studies have shown that postmenopausal women have higher serum TNF-alpha levels; however, whether this increase in TNF-alpha is associated with vascular dysfunction is unknown. We investigated whether estrogen deficiency is associated with increased serum TNF-alpha levels and tested the effects of in vivo TNF-alpha inhibition on vascular reactivity. Aged (12 to 15 months) Sprague-Dawley rats were ovariectomized and treated with placebo, estrogen, or a TNF-alpha inhibitor (Etanercept; 0.3 mg/kg) for 4 weeks. Serum TNF-alpha was determined by a bioassay, and vascular function was evaluated in the myograph system. Estrogen-deficient animals had higher serum levels of TNF-alpha compared with either estrogen-replaced animals or animals treated with Etanercept. Moreover, in estrogen-deficient rats, TNF-alpha inhibition reduced the constriction of mesenteric arteries to phenylephrine, increased the modulation of this vasoconstriction by the NO synthase inhibitor nitro-l-arginine methyl ester, and decreased the modulation by a superoxide scavenger (Mn(III)tetrakis(4-benzoic acid) porphyrin chloride). Furthermore, endothelium-dependent relaxation was also enhanced by TNF-alpha antagonism. Additionally, vascular expression of endothelial NO synthase was increased in animals treated with Etanercept, whereas the expression of NAD(P)H oxidase gp91phox and p22phox subunits was decreased. These data show that estrogen-deficient female rats have higher bioactive serum TNF-alpha levels compared with estrogen-replaced animals. Moreover, a decrease in serum bioactive TNF-alpha by a soluble TNF-alpha receptor (Etanercept) results in increased modulation of vascular function by NO. These observations suggest that TNF-alpha could be a mediator of vascular dysfunction associated with estrogen deficiency.

Octreotide ameliorates sepsis-induced pelvic inflammation in female rats by a neutrophil-dependent mechanism

Sepsis is a generalized inflammatory response, which involves organ systems remote from the locus of the initial infectious insult, accompanied by the release of cytokines and the subsequent formation of reactive oxygen and nitrogen species. The aim of this study was to investigate the possible protective effect of octreotide (OCT), a synthetic somatostatin analogue, against sepsis-induced oxidative damage in the uterine and ovarian tissues of rats. Sepsis was induced by caecal ligation and puncture method in female Wistar albino rats. Sepsis and sham operated (control) groups received either saline or OCT (50 μg/kg, i.p.; Novartis) immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and serum TNF-α levels and tissue malondialdehyde (MDA) content, glutathione (GSH) levels and myeloperoxidase (MPO) activity were determined in the uterus and ovaries. Oxidant-induced tissue fibrosis was determined by tissue collagen contents, while the extent of tissue injuries was analyzed microscopically. Sepsis increased serum TNF-α levels and resulted in decreased GSH levels and increased MDA levels, MPO activity and collagen contents in both the uterus and the ovaries ( p < 0.05–0.001) indicating the presence of the oxidative damage, as also confirmed by histological analysis. On the other hand, OCT administration reversed these oxidant responses and reduced the severity of microscopic damage ( p < 0.001). In conclusion, OCT protects against sepsis-induced oxidative injury of the uterine and ovarian tissues by diminishing neutrophil infiltration, an important source of oxygen free radicals. Our results suggest that OCT may be of therapeutic value in ameliorating sepsis-associated pelvic inflammation.

Butyric Acid Derivative Induces Allospecific T Cell Anergy and Prevents Graft-Versus-Host Disease

Graft-versus-host-disease (GVHD) is a common and potentially fatal complication following bone marrow transplantation. This study was initiated to test whether MEB [n-butyrate 2-(4-morpholinyl) ethyl butyrate hydrochloride], a derivative of the G1 blocker butyric acid, could specifically inactivate the alloantigen-specific T cells that mediate GVHD. MEB was shown to inhibit proliferation in a one-way mixed lymphocyte reaction (MLR) in which spleen cells from C57BL/6 mice (H-2b) were stimulated with spleen cells from DBA/2 mice (H-2d). The addition of MEB to the MLR prevented the expansion of alloantigen-stimulated CD8+ and CD4+ T cells in association with decreased IL-2 production. In addition, MEB inhibited the CTL activity of CD8+ T cells from the MLR. Most importantly, T cells from the MEB-treated MLR, unlike T cells from an untreated MLR, were unable to induce the splenomegaly and increased serum TNF-α levels characteristic of acute GVHD when injected into B6D2F1 mice. The splenomegaly found in the B6D2F1 mice injected with T cells from an untreated MLR encompassed the expansion and activation of CD8+ T cells, CD4+ T cells, B cells and macrophages. In contrast, the spleens of mice injected with T cells from MEB-treated MLR looked essentially identical to those of control B6D2F1 mice in terms of the numbers and activation state of the spleen cell populations. Similarly, the increase in IFN-γ and TNF-α production by CD4+ and CD8+ T cells from the spleens of mice undergoing acute GVHD was not observed if the mice were injected with T cells from an MEB-treated MLR instead of an untreated MLR. The use of MEB to inactivate host-specific T cells ex vivo underlines the potential clinical importance of this compound in the prevention and treatment of unwanted immune responses such as GVHD.

Increased tumor necrosis factor-alpha level in infertility patient

Objective: It is becoming increasingly apparent that a link between infertility and immune activity exists. Cytokines such as tumor necrosis factor (TNF-α) and those leading to a TH 1 type immune response are suspected of playing an important role not only in recurrent spontaneous abortions but also possibly in fertility. In this study, we examined the serum TNF-α levels of women with a history of infertility.Methods: Serum samples from women with a history of infertility, as well as normal adults were collected. TNF-α levels were measured by EIA.Results: The mean serum TNF-α level of normal controls was 2.6 + 1.4 pg/ml. In contrast, the serum TNF-α levels of women with infertility history were significantly increased (P < .05), ranging from 0.2 pg/mL to over 320 pg/mL. Furthermore, women with a history of infertility can be divided into two groups: TNF-α level of one group of patients (n=14) is within the range of normal control, 2.1 + 0.8 pg/ml. The other half (n=13) have TNF-α levels greater than the normal control mean plus 3 times standard deviation.Conclusion: TNF-α stratifies women with histories of infertility into 2 distinct groups and suggests a possible immune mechanism for some forms of infertility. This study indicates that a subgroup of women with infertility history has significantly increased serum TNF-α levels and the TNF-α can potentially serve as an infertility marker.

Induction of Proinflammatory Cytokine Expression in Experimental Acute Chagasic Cardiomyopathy

One of the hallmarks of Chagas' disease (caused byTrypanosoma cruzi) is progressive cardiomyopathy. The disease is associated with increased serum TNF-α levels, and TNF-α is known to depress cardiac function. It is, however, not known whether the cytokines are produced within the infected myocardium. One-month-old male Lewis rats were injected with cell culture-derivedT. cruzitrypomastigotes and killed 15 days post-infection. As compared to normal animals, histologic analysis of infected animals revealed dense infection with amastigotes within myocytes and a minimal inflammatory infiltrate in the myocardium. Northern blot analysis of total RNA revealed no signal for IL-1β or TNF-α,and a weak signal for IL-6 in the control rat hearts, and high levels of expression for the three genes in the infected rats. Western blots revealed results similar to that of mRNA levels, suggesting that, in addition to mechanical damage, infection byT. cruziinduces proinflammatory cytokine production in the myocardium itself, which may further exacerbate the pathology, and affect adversely myocardial function.