Increased Serum Tumor Necrosis Factor Research Articles

Prognostic values of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and neuron-specific enolase in patients with sepsis-associated encephalopathy

Background/Aim. Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, characterized by brain dysfunction and associated with a poor prognosis. SAE has a complex pathogenesis, and its severity is in close association with the levels of various serum factors. The aim of the study was to investigate the correlation of tumor necrosis factor (TNF)-?, monocyte chemoattractant protein (MCP)-1, and neuron-specific enolase (NSE) levels with the severity of SAE and to analyze the prognostic values of the three parameters. Methods. This prospective study enrolled 126 patients treated for SAE from June 2020 to June 2022. The levels of TNF-?, MCP-1, and NSE were measured, and the severity of SAE was evaluated using the Sequential Organ Failure Assessment (SOFA) score. Based on the SOFA score, the patients were assigned to two groups: a group with a bad prognosis and a group with a good prognosis. The correlations of TNF-?, MCP-1, and NSE levels with the severity of SAE were analyzed, and their prognostic values were evaluated during a 28-day follow-up. Results. The mean levels of TNF-?, MCP-1, and NSE and the SOFA score of the 126 patients with SAE were 6.52 ? 1.48 pg/mL, 62.53 ? 18.49 pg/mL, 8.61 ? 2.17 ng/mL, and 10.24 ? 2.86 points, respectively. Pearson?s analysis demonstrated significant correlations be-tween TNF-?, MCP-1, and NSE levels and the SOFA score of patients with SAE (r > 0, p < 0.05). Of the 126 patients, 61 (48.4%) had a poor prognosis, while 65 (51.6%) had a good prognosis. Increased serum TNF-?, MCP-1, and NSE levels were risk factors for the poor prognosis of patients with SAE [odds ratio (OR) > 1, p < 0.05]. The areas under the receiver operating characteristic (ROC) curves of serum TNF-?, MCP-1, and NSE levels were all > 0.7, suggesting high predictive values of these parameters. Conclusion. Serum TNF-?, MCP-1, and NSE levels are closely correlated with the severity of SAE and may work as valuable predictors of treatment outcome.

Exposure to triphenyltin impairs gut integrity, disturbs gut microbiota, and alters fecal metabolites

Triphenyltin is an environmental contaminant widely used in antifouling paints and can cause toxicity in various organs in living organisms. However, its effects on intestinal function and the microbiome of the gut remain unknown. The objective of this study was to explore the intestinal toxicity of triphenyltin in mice by orally administering 0, 1.875, 3.75, and 7.5 mg/Kg to adult male mice for 8 weeks. Results showed that triphenyltin caused ileum tissue damage, induced oxidative stress, upregulated inflammation-related gene expression and increased serum tumor-necrosis factor α (TNF-α) levels in mice. Triphenyltin impaired ileum barrier function by downregulating Muc2, ZO-1, Occludin and their protein levels at 3.75 and 7.5 mg/Kg. TPT exposure led to partial inflammation and decreased mucin mRNA expression in the colon. Triphenyltin altered intestinal micro-ecological balance and fecal metabolome in mice. In conclusion, triphenyltin alters the mouse gut microbiota and fecal metabolome.

Determination of acute toxicity of sodium pyrithione and its exposure effects on antioxidant enzymes activity, immune status, and histopathological changes in common carp

ABSTRACT This study determined the LC50-24 h value of sodium pyrithione (NaPT) on Cyprinus carpio at 102.7643 µg/L. Then, 60 healthy fish were randomly allocated into 6 exposure groups, each receiving varying levels of NaPT for different durations (control goup = 0% µg/L NaPT for 24 and 96 h; NaPT-10 = 10% of the LC50-24 h dose of NaPT for 24 and 96 h; NaPT-20 = 20% of the LC50-24 h dose of NaPT for 24 and 96 h). As a result, the increase in malondialdehyde (MDA) levels and the decrease in catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities in the gill and liver tissue in both duration and dose groups were found to be statistically significant. In addition, NaPT increased serum tumour necrosis factor (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) levels in both dose groups for both durations. The results revealed that NaPT exposure caused shortening of gill tissue lamellae and vacuolisation (separation) of the secondary lamellar epithelium. Likewise, NaPT exposure was responsible for vacuolisation and hepatocellular degeneration in liver tissue in hepatocytes. In conclusion, the toxicity study, antioxidant enzyme activities, cytokine immune response, and histopathological results indicate that NaPT has a toxic effect on the carp.

Serum cytokine levels in patients with hidradenitis suppurativa vary with race

To the Editor: Hidradenitis suppurativa (HS) is a chronic condition characterized by painful nodules and abscesses in intertriginous areas that can lead to disfigurement. The presumed immunopathogenesis of HS involves an exaggerated response to ruptured follicles. Aberrant cytokine expression has been demonstrated in the serum of patients with HS, specifically, increased serum tumor necrosis factor (TNF)-α,1 interleukin (IL)-17,2 and IL-1β.3 Although biologics targeting TNF-α and IL-1 have shown success, the quest for additional treatment options remains ongoing.

Experimental arthritis and Porphyromonas gingivalis administration synergistically decrease bone regeneration in femoral cortical defects

Porphyromonas gingivalis infection can lead to periodontitis and dysbiosis, which are known risk factors for rheumatoid arthritis (RA). We investigated whether P. gingivalis administration affected bone regeneration in mice with or without arthritis. We administered P. gingivalis to male DBA/1 J mice that were or were not sensitised to type II collagen-induced arthritis (CIA). All mice underwent drilling of bilateral femurs. We histologically evaluated new bone regeneration (bone volume of the defect [BVd]/tissue volume of the defect [TVd]) using micro-computed tomography (micro-CT), osteoclast number/bone area, and active osteoblast surface/bone surface (Ob.S/BS). We measured serum cytokine levels and bone mineral density of the proximal tibia using micro-CT. CIA resulted in significantly reduced bone regeneration (BVd/TVd) at all time-points, whereas P. gingivalis administration showed similar effects at 2 weeks postoperatively. CIA resulted in higher osteoclast number/bone area and lower Ob.S/BS at 2 and 3 weeks postoperatively, respectively. However, P. gingivalis administration resulted in lower Ob.S/BS only at 2 weeks postoperatively. During later-stage bone regeneration, CIA and P. gingivalis administration synergistically decreased BVd/TVd, increased serum tumour necrosis factor-α, and resulted in the lowest bone mineral density. Therefore, RA and dysbiosis could be risk factors for prolonged fracture healing.

Premarin has opposing effects on spatial learning, neural activation, and serum cytokine levels in middle-aged female rats depending on reproductive history

Menopause is associated with cognitive decline, and hormone therapies (HTs) may improve cognition depending on type and timing of HTs. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin 6 months later, and all rats were trained in the Morris water maze. Premarin improved early spatial learning and memory in nulliparous rats but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor α and the CXC chemokine ligand 1 (CXCL1) in trained nulliparous, but not primiparous, rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women.

Effect of Lipopolysaccharide-Induced Immune Responses on Pregnancy Loss in Ewes

An acute phase response induced by Gram-negative bacteria can reduce pregnancy rate. Early pregnant ewes were used to monitor effects of lipopolysaccharide (LPS), an endotoxin in the outer cell membrane of Gram-negative bacteria, on acute phase/innate immunity response. In Exp. 1, mixed breed ewes were assigned to receive either LPS or LPS and flunixin meglumine, an inhibitor of prostaglandin synthetase, intravenously on day 5 after mating. In Exp. 2, mixed breed ewes were assigned to receive an intravenous injection on day 5 after mating of either saline, LPS, recombinant human tumor necrosis factor (TNF)-α or LPS after pretreatment with dexamethasone. Pregnancy was diagnosed ultrasonographically on d 25, and live births were recorded at parturition. Challenge with LPS induced acute phase responses (fever, mucosal responses, lethargy and increased serum TNF, haptoglobin and serum amyloid A) and decreased pregnancy rates. Predictably, flunixin meglumine attenuated fever but did not increase pregnancy rate in LPS-treated ewes. Similarly, exogenous TNF alone induced mucosal and serum amyloid A responses but did not affect pregnancy. Pre-treatment with dexamethasone blocked fever and mucosal and lethargic responses and attenuated increases in TNF and haptoglobin but did not ameliorate LPS-induced pregnancy loss. In summary, acute challenge with LPS mimics bacterial-induced pregnancy losses in early pregnant ewes. Although pretreatment with dexamethasone decreased clinical signs and some innate immune responses, neither it nor flunixin meglumine prevented LPS-induced pregnancy loss. That exogenous TNF alone did not promote pregnancy loss indicates that other cytokines also contribute to LPS-induced embryonic loss.

Perinatal ciclosporin A exposure elicits sex-related cardiac dysfunction and inflammation in the rat progeny

Ciclosporin A (CSA) has been identified with harmful cardiotoxicity but little, if any, is known about the influence of perinatal exposure upon the cardiac function of the progeny. The present work examines the premise that perinatal contact with CSA undermines the cardiac function of sexually mature rats. Administration of CSA (15mg/kg/day sc) to pregnant rats from day 6 of conception till weaning led to a decrease in gradient of the end-systolic pressure-volume relationship by a factor of ten for male progeny and a factor of two for female progeny. Perinatally CSA-exposed male, but not female, progeny also demonstrated significantly increased systolic and diastolic blood pressure, along with significantly increased JT interval and a tendency towards increased QTc interval, indicating delayed left ventricular (LV) repolarization and perhaps arrhythmogenesis. Conversely, female, but not male, progeny exposed perinatally to CSA showed a delay in atrioventricular (AV) conduction, as demonstrated by significantly prolonged P duration and a tendency towards increased PR interval. CSA increased serum tumor necrosis factor α (TNFα) and decreased serum adiponectin levels and cardiac adiponectin receptor expression in male progeny, in contrast to no effects in female progeny. Signs of improved oxidative state (decreased 8-isoprostane and increased catalase activity) appeared only in CSA-exposed female rats. Moreover, cardiac muscle degeneration and pyknosis was more observed in male than in female rats. In brief, the sex plays a key role in determining the extent of the deterioration in functional and inflammatory states of the heart that follow perinatal CSA exposure in rats.

Proposed mechanisms for oligonucleotide IMT504 induced diabetes reversion in a mouse model of immunodependent diabetes.

Type 1 diabetes (T1D) originates from autoimmune β-cell destruction. IMT504 is an immunomodulatory oligonucleotide that increases mesenchymal stem cell cloning capacity and reverts toxic diabetes in rats. Here, we evaluated long-term (20 doses) and short-term (2-6 doses) effects of IMT504 (20 mg·kg(-1)·day(-1) sc) in an immunodependent diabetes model: multiple low-dose streptozotocin-injected BALB/c mice (40 mg·kg(-1)·day(-1) ip for 5 consecutive days). We determined blood glucose, glucose tolerance, serum insulin, islet morphology, islet infiltration, serum cytokines, progenitor cell markers, immunomodulatory proteins, proliferation, apoptosis, and islet gene expression. IMT504 reduced glycemia, induced β-cell recovery, and impaired islet infiltration. IMT504 induced early blood glucose decrease and infiltration inhibition, increased β-cell proliferation and decreased apoptosis, increased islet indoleamine 2,3-dioxygenase (IDO) expression, and increased serum tumor necrosis factor and interleukin-6 (IL-6). IMT504 affected islet gene expression; preproinsulin-2, proglucagon, somatostatin, nestin, regenerating gene-1, and C-X-C motif ligand-1 cytokine (Cxcl1) increased in islets from diabetic mice and were decreased by IMT504. IMT504 downregulated platelet endothelial cell adhesion molecule-1 (Pecam1) in islets from control and diabetic mice, whereas it increased regenerating gene-2 (Reg2) in islets of diabetic mice. The IMT504-induced increase in IL-6 and islet IDO expression and decreased islet Pecam1 and Cxcl1 mRNA expression could participate in keeping leukocyte infiltration at bay, whereas upregulation of Reg2 may mediate β-cell regeneration. We conclude that IMT504 effectively reversed immunodependent diabetes in mice. Corroboration of these effects in a model of autoimmune diabetes more similar to human T1D could provide promising results for the treatment of this disease.

Increased serum tumor necrosis factor receptor-associated factor-6 expression in patients with non-metastatic triple-negative breast cancer.

Obesity appears to be associated with an increased risk of breast cancer (BC) and an inferior oncological outcome at the time of diagnosis, with poor outcomes most prominent in cases of triple-negative BC (TNBC). The present study analyzed serum tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and TNF receptor associated factor-6 (TRAF) protein expression levels in 48 patients with non-metastatic BC and 26 obese control patients (without BC). The mean age of the cohort was 52.5 years (range, 35-78 years) and the patients had a median body mass index of 33.5 kg/m2 (range, 30-47 kg/m2). In the study population, 27.1% of BC patients were triple negative and 70.8% were hormone receptor (HR)-positive. Median serum TRAF6 expression was 0.90 ng/ml (range, 0.55-1.53 ng/ml) in the 13 TNBC patients and 0.63 ng/ml (range, 0.49-1.22 ng/ml) in the 35 HR-positive BC patients; thus, TRAF6 expression was significantly higher in the TNBC patients compared with the obese control group (0.90 vs. 0.73 ng/ml; P=0.033). Furthermore, median serum TRAF6 expression levels were significantly higher in HR-negative patients compared with HR-positive patients (0.83 vs. 0.62 ng/ml; P=0.002). The present study demonstrated that serum TRAF6 expression levels were increased in TNBC and HR-negative patients with non-metastatic BC compared with HR- and human epidermal growth factor receptor 2-positive cases or the obese healthy control group. Therefore, elevated TRAF6 expression may be a poor prognostic factor in non-metastatic BC. In addition, we propose that progesterone (PR) negativity may be a more useful poor prognosis factor than estrogen receptor (ER) negativity, as TRAF6 expression levels were higher in the PR-negative patients compared with the ER-negative patients.

Life or death by NFκB, Losartan promotes survival in dy2J/dy2J mouse of MDC1A.

Inflammation and fibrosis are well-defined mechanisms involved in the pathogenesis of the incurable Laminin α2-deficient congenital muscular dystrophy (MDC1A), while apoptosis mechanism is barely discussed. Our previous study showed treatment with Losartan, an angiotensin II type I receptor antagonist, improved muscle strength and reduced fibrosis through transforming growth factor beta (TGF-β) and mitogen-activated protein kinases (MAPK) signaling inhibition in the dy2J/dy2J mouse model of MDC1A. Here we show for the first time that Losartan treatment up-regulates and shifts the nuclear factor kappa B (NFκB) signaling pathway to favor survival versus apoptosis/damage in this animal model. Losartan treatment was associated with significantly increased serum tumor necrosis factor alpha (TNF-α) level, p65 nuclei accumulation, and decreased muscle IκB-β protein level, indicating NFκB activation. Moreover, NFκB anti-apoptotic target genes TNF receptor-associated factor 1 (TRAF1), TNF receptor-associated factor 2 (TRAF2), cellular inhibitor of apoptosis (cIAP2), and Ferritin heavy chain (FTH1) were increased following Losartan treatment. Losartan induced protein expression toward a pro-survival profile as BCL-2 expression levels were increased and Caspase-3 expression levels were decreased. Muscle apoptosis reduction was further confirmed using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. Thus, along with TGF-β and MAPK signaling, NFκB serves as an important regulatory pathway which following Losartan treatment promotes survival in the dy2J/dy2J mouse model of MDC1A.

Increased serum tumor necrosis factor α levels in patients with lenalidomide-induced hypothyroidism

Increased serum tumor necrosis factor α levels in patients with lenalidomide-induced hypothyroidism

β-caryophyllene protects against D-galactosamine and lipopolysaccharide-induced hepatic failure

β-caryophyllene (4,11,11-trimethyl-8-methylene-bicyclo[7.2.0]undec-4-ene) is a natural bicyclic sesquiterpene isolated from Agastache rugosa (Fisch. et Meyer) O. Kuntze (Labiatae) has been shown to exhibit antioxidant and anti-inflammatory properties. Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive inflammation and hepatocellular death. Inflammasome plays an important role in the regulation of cellular redox balance, apoptosis, and inflammation in the FHF. In this study, we examined the hepatoprotective mechanisms of β-caryophyllene against D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic failure. Mice were given an intraperitoneal injection of β-caryophyllene (50, 100 and 200 mg/kg) or vehicle alone (10% Tween 80 saline) 1h before GalN (800 mg/kg)/LPS (40 µg/kg), and sacrificed at 1 and 6h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity, which were attenuated by β-caryophyllene. GalN/LPS increased serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels, and these increases were attenuated by β-caryophyllene. GalN/LPS significantly increased protein expression of toll-like receptor (TLR) 4, myeloid differentiation primary response gene 88 and TNF receptor-associated factor 6, nuclear protein expression of nuclear factor kB, and these increases were attenuated by β-caryophyllene. GalN/LPS activated NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome as indicated by increased mature IL-1β, caspase-1, apoptosis-associated speck-like protein containing a CARD, and NLRP3 protein expressions. This activation was attenuated by β-caryophyllene. Our finding suggests that β-caryophyllene protects against GalN/LPS-induced liver injury through suppression of TLR4 signaling and inflammasome pathway.

Increased serum tumor necrosis factor α levels in patients with lenalidomide-induced hypothyroidism

As the use of lenalidomide expands, the poorly understood phenomenon of lenalidomide-induced thyroid abnormalities will increase. In this study, we compared rates of therapy-induced hypothyroidism in 329 patients with diffuse large B-cell lymphoma (DLBCL) treated with conventional chemotherapy (DLBCL-c) or conventional chemotherapy plus lenalidomide (DLBCL-len). We measured serum levels of tumor necrosis factor α, interferon gamma, interleukin 6, interleukin 12, and interleukin 15 before and after treatment. We found a significantly higher rate of therapy-induced hypothyroidism in the DLBCL-len group (25.8% vs. 1.3%), and we found a statistically significant increase in serum tumor necrosis factor α in patients with lenalidomide-induced hypothyroidism.

Exercise training attenuates cerebral ischemic hyperglycemia by improving hepatic insulin signaling and β-cell survival

AimsPreventing hyperglycemia after acute stroke attenuates complications of cerebral ischemia and reduces the risk of mortality. We investigated whether regular exercise prevents neuronal cell death and post-stroke hyperglycemia in gerbils after cerebral ischemia. Main methodsCerebral ischemia was induced by carotid artery occlusion for 8min. The gerbils that underwent ischemic or sham operations were randomly subdivided into exercise (ran on inclined treadmill at 20m/min for 30min 5days per week for 1week prior to surgery) or non-exercise groups. Gerbils were fed a 40% fat diet and after 28days, glucose metabolism, serum cytokine levels and cognitive function was measured. Key findingsArtery occlusion resulted in a 64% reduction in hippocampal CA1 neurons in comparison to the sham gerbils, and caused decreased neuronal mass and impaired cognitive function. Exercise partially prevented neuronal death and improved ischemia-induced glucose intolerance. Ischemia decreased hepatic insulin signaling and exacerbated insulin resistance whereas exercise prevented the disturbance. Insulin secretion was lower in ischemic gerbils than sham gerbils, due to lowered pancreatic β-cell mass caused by increased β-cell apoptosis and decreased β-cell proliferation, which were also prevented by exercise. Increase of apoptosis was associated with elevated caspase-3 activity, consistent with increased serum tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels. SignificanceHippocampal neuronal cell death induces hyperglycemia due to attenuated hepatic insulin signaling and decreased β-cell mass by increased β-cell apoptosis through increased TNF-α and IL-1β levels. Exercise partially prevents this phenomenon suggesting that exercise training may provide neuroprotective benefits from cerebral ischemic hyperglycemia.

Inhibition of CCL20 increases mortality in models of mouse sepsis with intestinal apoptosis

CC chemokine ligand 20 (CCL20) and CC chemokine receptor 6 are believed to stimulate the recruitment of neutrophils and activation of macrophages against bacterial pathogens through the activation of T helper cells. We analyzed the role of CCL20 in the acute phase of sepsis. The effect of a neutralizing, anti-mouse CCL20 monoclonal antibody (mAb) was examined in 2 murine models of sepsis: Cecal ligation and puncture (CLP) and Escherichia coli peritonitis. Immune cell migration, bacterial clearance, and expression of 17 cytokines and 5 chemokines were quantified in Ecoli-induced peritonitis. Expression of CCL20 in various tissues was determined, and apoptotic cells in jejunum were measured. Anti-CCL20 mAb increased mortality in CLP and E coli peritonitis (P = .029 and .024, respectively by Kaplan-Meier method and log-rank test). The 48-hour survival rate in anti-CCL20 mAb- and control immunoglobulin (Ig)G-treated mice was 37% (11/30) vs 62% (18/29) in CLP and 28% (11/40) vs 48% (19/40) in bacterial peritonitis. Neutralization of CCL20 showed no effect on leukocyte infiltration into the peritoneal cavity or bacterial clearance at 24 hours. CCL20 was induced strongly and predominantly in jejunum after bacterial infection, and neutralizing CCL20 increased apoptosis of epithelial cells in jejunum crypt. Inhibition of CCL20 increased serum tumor necrosis factor (TNF)-α (3.3-fold greater than control mice) and decreased serum interleukin (IL)-1α and IL-6. Neutralization of CCL20 before induction of sepsis increased mortality during sepsis accompanied with increasing epithelial apoptosis in the jejunum and augmenting serum TNF-α.

Tumour Necrosis Factor-Alpha Gene Expression in Chronic Hepatitis C Virus Infection.

Objective: Tumour necrosis factor (TNF)-alpha, a prototype proinflammatory cytokine, has been implicated as an important pathogenic mediator in a variety of liver conditions. Some genetic polymorphisms in the human TNF-alpha promoter region, such as the G-A transitions -308 and – 238, have been shown to influence TNF-alpha expression in chronic hepatitis C virus infection. Aim of the work: The present study was to investigate the influence that the – 308and – 238 TNF- alpha promoter polymorphisms have on the response to interferon and ribavirin therapy in chronic hepatitis C virus infection. Patients and methods: One hundred forty patients with chronic hepatitis C virus infection, their age ranges between (20-56) years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, during interferon and ribavirin therapy and thirty five healthy individuals were included to serve as controls, the patients and controls were divided into two groups the first group forty patients and fifteen controls for the detection of TNF-alpha -308, -238 genotypes polymorphisms, the second group were one hundred patients and twenty healthy controls for the detection of serum levels of TNF-α. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation, CBCs and serological assay, genotyping of 308, 238 TNF-alpha promoter polymorphism and serum levels of TNF-α. Results: There was no statistically significant difference between chronic HCV patients and healthy controls as regarding TNF-alpha -238 different alleles. The frequencies of TNF-alpha gene polymorphism with A/G and G/G mutation at – 308 were significantly higher in chronic HCV patients than those in the controls. The serum level of TNF-alpha was markedly higher in the chronic HCV patients than in the healthy controls. There were significant association between TNF- alpha gene polymorphism in the – 308 A/G, G/G alleles and increased serum TNF- alpha in CHCV infection. Conclusion: The results indicate that the TNF-alpha gene polymorphism at position -308 is associated with susceptibility of chronic HCV infection. Recommendations: Our major concern was to improve the response to treatment in patients with chronic HCV infection, whether the disadvantage of having the TNF-alpha -308 allele became more apparent after interferon and ribavirin therapy is unclear and needs further study that detecting the polymorphism of the -308 TNF-alpha allele before administering interferon therapy may be valuable for predicting the treatment response, especially in difficult- to treat patients.

Tumour Necrosis Factor-Alpha Gene Expression in Chronic Hepatitis C Virus Infection.

Objective: Tumour necrosis factor (TNF)-alpha, a prototype proinflammatory cytokine, has been implicated as an important pathogenic mediator in a variety of liver conditions. Some genetic polymorphisms in the human TNF-alpha promoter region, such as the G-A transitions -308 and – 238, have been shown to influence TNF-alpha expression in chronic hepatitis C virus infection. Aim of the work: The present study was to investigate the influence that the – 308and – 238 TNF- alpha promoter polymorphisms have on the response to interferon and ribavirin therapy in chronic hepatitis C virus infection. Patients and methods: One hundred forty patients with chronic hepatitis C virus infection, their age ranges between (20-56) years, selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, during interferon and ribavirin therapy and thirty five healthy individuals were included to serve as controls, the patients and controls were divided into two groups the first group forty patients and fifteen controls for the detection of TNF-alpha -308, -238 genotypes polymorphisms, the second group were one hundred patients and twenty healthy controls for the detection of serum levels of TNF-α. All the patients and controls were subjected to the following history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation, CBCs and serological assay, genotyping of 308, 238 TNF-alpha promoter polymorphism and serum levels of TNF-α. Results: There was no statistically significant difference between chronic HCV patients and healthy controls as regarding TNF-alpha -238 different alleles. The frequencies of TNF-alpha gene polymorphism with A/G and G/G mutation at – 308 were significantly higher in chronic HCV patients than those in the controls. The serum level of TNF-alpha was markedly higher in the chronic HCV patients than in the healthy controls. There were significant association between TNF- alpha gene polymorphism in the – 308 A/G, G/G alleles and increased serum TNF- alpha in CHCV infection. Conclusion: The results indicate that the TNF-alpha gene polymorphism at position -308 is associated with susceptibility of chronic HCV infection. Recommendations: Our major concern was to improve the response to treatment in patients with chronic HCV infection, whether the disadvantage of having the TNF-alpha -308 allele became more apparent after interferon and ribavirin therapy is unclear and needs further study that detecting the polymorphism of the -308 TNF-alpha allele before administering interferon therapy may be valuable for predicting the treatment response, especially in difficult- to treat patients.

Activation of nuclear factor-kappa B accelerates vascular calcification by inhibiting ankylosis protein homolog expression

Vascular calcification is a major risk factor of cardiovascular mortality, particularly for patients with end-stage renal disease and diabetes. Although chronic inflammation is one of the etiologic factors, the underlying mechanism is not fully understood. To clarify this, we studied how nuclear factor-kappa B (NF-κB) induction, a mediator of inflammation, might promote vascular calcification. Activation of NF-κB by tumor necrosis factor (TNF) promoted inorganic phosphate-induced calcification in human aortic smooth muscle cells. Pyrophosphate (an inhibitor of calcification) efflux to the extracellular matrix was suppressed along with the decreased expression of ankylosis protein homolog (ANKH), a transmembrane protein that controls pyrophosphate efflux of cells. The restoration of ANKH expression in these cells overcame the decreased pyrophosphate efflux and calcification. Tristetraprolin, a downstream product of NF-κB activation, may mediate destablization of ANKH mRNA since its knockdown by shRNA increased ANKH expression and decreased calcification. Furthermore, a rat chronic renal failure model, with increased serum TNF levels, activated NF-κB and decreased ANKH levels. In contrast, the inhibition of NF-κB maintained ANKH expression and attenuated vascular calcification both in vivo and in vitro. Both human calcified atherosclerotic lesions and arteries from patients with chronic kidney disease had activated NF-κB and decreased ANKH expression. Thus, TNF-activated NF-κB promotes inflammation-accelerated vascular calcification by inhibiting ankylosis protein homolog expression and consequent pyrophosphate secretion.

Identification of Pigment Epithelium-Derived Factor as an Adipocyte-Derived Inflammatory Factor

Obesity is a major risk factor for insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The pathophysiology of obesity is associated with chronic low-grade inflammation. Adipose tissue in obesity is significantly infiltrated by macrophages that secrete cytokines. The mechanisms of interaction between macrophages and adipocytes, leading to macrophage activation and increased cytokine release, remain to be elucidated. We reasoned that an adipocyte-derived factor might stimulate activation of macrophages. We have identified pigment epithelium-derived factor (PEDF) as a mediator of inflammation that is secreted by adipocytes and mediates macrophage activation. Recombinant PEDF activates macrophages to release tumor necrosis factor (TNF) and interleukin-1 (IL-1). The PEDF receptor adipose triglyceride lipase (ATGL) is required for PEDF-mediated macrophage activation. Selective inhibition of ATGL on macrophages attenuates PEDF-induced TNF production, and PEDF enhances the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. PEDF administration to rats results in increased serum TNF levels, and insulin resistance. Together, these findings suggest that PEDF secreted by adipocytes contributes to the onset and maintenance of chronic inflammation in obesity, and may be a therapeutic target in ameliorating insulin resistance.