Soluble TNF Receptor Levels Research Articles

Effects of AM3 (Inmunoferon®) on increased serum concentrations of interleukin-6 and tumour necrosis factor receptors I and II in cyclists

The aims of this study were to examine the changes in plasma concentrations of inflammatory cytokines induced by training and competition in professional cyclists. We report the serum concentrations of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), tumour necrosis factor receptors I and II (TNFR-I and -II) in a prospective, randomized, double-blind trial involving the administration of AM3 (Inmunoferon®), an oral booster immunomodulator, or placebo to 16 professional cyclists (n=8 in each group) for 65 consecutive days. Serum was collected just before treatment began (baseline), at the end of pre-competition training, before the mountain stage of the competition (60 days), 4 h after finishing this stage (62 days), and 18 h after the fifth and last day of competition (65 days). To determine the normal levels of cytokines and soluble TNF receptors, individual samples from 14 moderately trained healthy controls were studied. After 60 days of training, the serum concentrations of IL-6 did not differ significantly from those at the beginning of the study for either group of cyclists (placebo and AM3). A significant rise was seen in IL-6 concentrations in both the AM3 and placebo groups at 62 days, 4 h after finishing the mountain stage. The increase was significantly greater in the placebo group than in the AM3 group. At 65 days of treatment, 18 h after the fifth and last day of competition, IL-6 concentrations were similar to those recorded at the end of the training, but were significantly higher in the placebo group than in the AM3 group. At the end of training, serum TNFR-I concentrations in both groups of cyclists were significantly lower than at baseline. The concentrations of serum TNFR-I and -II both 4 h after finishing the mountain stage and 18 h after the fifth and last day of competition were significantly higher than those recorded after training in both groups. Professional cycling competition is associated with increases in serum IL-6 and TNFR-I and -II concentrations. Inmunoferon treatment reduced significantly the concentrations of IL-6 but not those of TNFR-I and -II.

Endogenous inhibitory cytokines repress TNFα secretion

Tumor necrosis factor α (TNFα), with the potential to destroy tissue, is likely to be tightly regulated. A major regulatory step is the translational repression of TNFα. This study evaluates whether endogenous inhibitory cytokines account for this repression. Two cell populations were isolated from peripheral blood using techniques that minimized activation, one composed primarily of monocytes and the other containing T-cells and NK-cells. When cultured without a stimulus in the presence of Abs neutralizing IL-4, IL-10, or TGFβ, each population released large amounts of TNFα, reaching levels induced by PHA or LPS. Their actions were at the post-translational level since the numbers of transcripts did not change, and inhibitors of protein or RNA synthesis had no effects. When inhibitors of 38 MAP kinase and ERK were added, T-cell release of TNFα proved to involve both pathways while monocytes were dependent on p38 but not ERK. Changes in soluble TNF receptor levels or cell uptake of TNFα were not involved. This study shows that low TNFα secretion by resting T-cells and monocytes is maintained by endogenous inhibitors that suppress post-translational processing of TNFα by MAP kinases. Keeping TNFα levels low is critical to the non-inflammatory steady-state.

Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury

Ventilator-induced lung injury (VILI) is an inflammatory process that can be attenuated by lung protective ventilation strategies. Our objectives to further investigate the pathogenesis of ALI and VILI and the mechanism of lung protection in these syndromes were: 1) to determine if plasma measurements of soluble TNF receptor I (sTNFRI) and II (sTNFRII) would predict the development of ALI and mortality in a small single center trial; 2) to test the predictive value of these markers and of TNF-alpha in a larger, broader group of patients with ALI; 3) to test the hypothesis that low tidal volume ventilation (LTVV) would be associated with a decrease in plasma levels of TNF-alpha, sTNFRI, and sTNFRII. In the single center study, sTNFRI and II levels were higher in patients at risk for and with ALI, but they did not predict the development of the syndrome. In the multicenter trial sTNFRI and II were strongly associated with mortality (OR 5.76/1 log10 increment in receptor level; 95% CI 2.63-12.6 and OR 2.58; 95% CI 1.05-6.31, respectively) and morbidity measured as fewer nonpulmonary organ failure-free and ventilator-free days. The LTVV strategy was associated with an attenuation of plasma sTNFRI levels. In vitro, stimulated A549 cells release sTNFRI but not sTNRFII. In conclusion, plasma levels of sTNFRI and II can serve as biomarkers for morbidity and mortality in patients with ALI. Furthermore, LTVV is associated with a specific decrease in sTNFRI levels. This suggests that one beneficial effect of LTVV may be to attenuate alveolar epithelial injury.

Tumor necrosis factor–α–induced insulin resistance may mediate the hepatitis C virus–diabetes association

Objectives Among patients infected with hepatitis C virus (HCV), 13–33% develop type 2 diabetes mellitus (DM). The mechanism for this remains unclear. Because tumor necrosis factor–α (TNF-α) has been identified as a mediator of insulin resistance and is induced by HCV, we examined TNF-α and proinflammatory cytokines in noncirrhotic patients with chronic hepatitis C, both with and without diabetes. Methods HCV-infected patients with type 2 DM (n = 23) were compared with age- and sex-matched patients with chronic hepatitis C and without DM (n = 28), patients with DM and without HCV (n = 31), and healthy controls (n = 21). Serum levels of TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6), and soluble TNF receptors (sTNFR) 1 (p55) and 2 (p75) were determined by ELISA. Results Detectable serum TNF was found in 74% of the HCV/DM patients, versus 64% of the nondiabetic HCV group and ≤10% in the other groups. Mean sTNFR1 in the HCV/DM group was 1931 pg/ml (95% CI = 1449–2413), compared with 1289 pg/ml (95% CI = 1101–1476) in nondiabetic HCV patients, with similar values in the other two groups ( p = 0.001). The mean sTNFR2 level in the HCV/DM patients was 3326 pg/ml (95% CI = 2924–3727) compared with 2367 pg/ml (95% CI = 1951–2784) in the nondiabetic HCV patients, and similar results in the other groups ( p < 0.0001). Serum IL-1β, IL-6, and C-reactive protein were not significantly different between HCV patients with or without DM. Conclusions Excessive TNF-α response characterizes HCV-infected patients who develop DM. STNFR may be a marker for the development of DM in chronic hepatitis C.

Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association.

Among patients infected with hepatitis C virus (HCV), 13-33% develop type 2 diabetes mellitus (DM). The mechanism for this remains unclear. Because tumor necrosis factor-alpha (TNF-alpha) has been identified as a mediator of insulin resistance and is induced by HCV, we examined TNF-alpha and proinflammatory cytokines in noncirrhotic patients with chronic hepatitis C, both with and without diabetes. HCV-infected patients with type 2 DM (n = 23) were compared with age- and sex-matched patients with chronic hepatitis C and without DM (n = 28), patients with DM and without HCV (n = 31), and healthy controls (n = 21). Serum levels of TNF-alpha, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and soluble TNF receptors (sTNFR) 1 (p55) and 2 (p75) were determined by ELISA. Detectable serum TNF was found in 74% of the HCV/DM patients, versus 64% of the nondiabetic HCV group and < or =10% in the other groups. Mean sTNFR1 in the HCV/DM group was 1931 pg/ml (95% CI = 1449-2413), compared with 1289 pg/ml (95% CI = 1101-1476) in nondiabetic HCV patients, with similar values in the other two groups (p = 0.001). The mean sTNFR2 level in the HCV/DM patients was 3326 pg/ml (95% CI = 2924-3727) compared with 2367 pg/ml (95% CI = 1951-2784) in the nondiabetic HCV patients, and similar results in the other groups (p < 0.0001). Serum IL-1beta, IL-6, and C-reactive protein were not significantly different between HCV patients with or without DM. Excessive TNF-alpha response characterizes HCV-infected patients who develop DM. STNFR may be a marker for the development of DM in chronic hepatitis C.

Immune dysregulation in Ethiopian immigrants in Israel: relevance to helminth infections?

The infectious disease background and particularly the helminth infections that are endemic in Africa could have profound effects on the host immune system. Studies that we have performed on an Ethiopian HIV- immigrant population that has recently reached Israel, lend support to this notion. They have indeed revealed a very high prevalence of helminth and several other infections with an extreme immune dysregulation, consisting of: (i) highly elevated plasma IgE, IgG, placental isoferritin, p75 soluble TNF receptor (sTNFR) levels and very high blood eosinophilia; (ii) increased secretion from phytohaemagglutinin (PHA)-simulated peripheral blood mononuclear cells (PBMC) of the cytokines IL-2, IL-4, IL-10 and p75 sTNFR, and decreased secretion of interferon-gamma (IFN-gamma) and IL-6; (iii) increased and decreased surface expression of p75 TNFR and IL-6 receptor on lymphocytes, respectively. The causal relationship between this immune dysregulation and the infectious background is highly suggestive, and could have far-reaching implications in the resistance to other infections.

Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis

Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor α (TNF-α) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-α in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-α, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-α production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-α levels, and in vitro TNF-α production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-α, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-α and sTNFR levels. In vitro TNF-α production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-α levels were further increased and in vitro TNF-α production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-α and sTNFR levels in cirrhosis. H epatology 2003;37:1154-1164.)

Troglitazone reduces fibrosis formation and progression in an experimental model of chronic pancreatitis in mice

Trogftazone reduces fibrosis formation and progression in an experimental model of chronic pancreatitis in mice. Background: Peroxisome proliferator activated receptor gamma (PFARgamma) conu~:~ls growth, dilferentistion, and inflammation. Aim: To determine the influence of troglitazone, a figand for PPAR-gamma, on fibrosis and pancreatic damage in a mouse model of chronic pancreatitis. Methods: Mice received six hourly intraperitoneal injections ~4th 50 mg/kg cerulein (to induce pancreatins) or NACL (control), three times a week for six weeks. Seven weeks after the first injection all mice were sacrificed, Five groups were compared, i.e. A: NACL injections, B: NACL injections, chow' mixed with 0.2% troglitazone, C: cerulein iujections, D: cerulein injections, chow mLxed with troglitasone, E: cerulein injections, chow mixed with troglitazone during last 3 weeks only,. End points were pancreas weight, pancreas histology (abnormal architecture, glandular atrophy, pseudotubular complexes), collagen formation (sirius red staining to quantify fibrosis; image analysis), pancreas amylase and hydroxyproline content, TGF beta (in pancreas and plasma), and plasma soluble TNF receptor levels. The number of activated stellate cells was detected by immunohistochemistry. Results: Group C had developed chronic panereatitis after 7 weeks (all parameters P < 0.05, C vs At. Troglitazone given either for seven weeks or only for the last three weeks, reduced pancreatic damage (histology, amylase and hydroxyproline content), collagen formation, TGF beta and sTNF receptor levels and the number of activated stellate cells (P<O.05, D or E vs C; nonsignificant for D vs E). Conclusion: Troglitazone blocks activation of pancreatic stellate cells and reduces fibrosis formation and pancreatic damage in experimental chronic pancreatitis Troglitazone remains beneficial in a therapeutic setting when given after initial da:nage has been established.

Association between levels of TNF-alpha and TNF-alpha promoter -308 A/A polymorphism in children with Kawasaki disease.

Tumor necrosis factor-alpha (TNF-alpha) has been shown to play a central role in the pathogenesis of vasculitis in Kawasaki disease (KD). We investigated the serum levels of TNF-alpha and soluble TNF receptor 1 (STNFR1) levels, and genetic polymorphisms of the TNF-alpha promoter gene in children with KD to delineate the genetic basis of KD. A total of 18 children (12 boys and 6 girls) with KD were studied, 9 of whom had the complication of coronary artery lesion (CAL) within 30 days after the onset of symptoms. Serum levels of TNF-alpha and STNFR1 were assayed by enzyme-linked immnosorbent assay, and DNA polymorphisms of the 5' flanking region of TNF-alpha promoter gene at position -308 [guanine (G) to adenine (A)] and -238 (G to A) were studied by direct nucleotide sequencing. The serum TNF-alpha level in KD patients was 113 +/- 209.9 pg/mL (range, 2.0 to 756.9 pg/mL; median, 24.7 pg/mL; normal, < 10 pg/mL). The serum levels of STNFR1 in KD (4255 +/- 2425 pg/mL) were higher than those of the control group (160 +/- 116 pg/mL). Allele frequencies of -308A and -238A were 11.1% and 0% in the KD patients, and 0% and 3.1% in the control group. Neither TNF-alpha promoter polymorphism nor any significant risk factor for CAL was identified in KD patients. One patient, who was homozygous for -308A, showed the highest TNF-alpha level and elevated STNFR1 level but had no evidence of CAL. Positive correlations were found between serum levels of STNFR1 and C-reactive protein (r = 0.731, p = 0.007), and between STNFR1 and leukocyte counts at admission (r = 0.620, p = 0.008). Increased serum levels of TNF-alpha and STNFR1 were found in KD patients but there was no correlation between these levels. The relationship between the pathogenesis of KD and TNF-alpha gene promoter -308G to A mutation towards cytokine production remains to be clarified.

Le TNF-receptor associated periodic syndrome (TRAPS) : aspects cliniques et physiopathologiques d'une maladie familiale rare

Hereditary periodic fever syndromes are defined as recurrent attacks of generalized inflammation for which no infectious or auto-immune cause can be identified. Minimal clinical variations, a unique biochemical-specific abnormality and the mode of genetic inheritance distinguish the four main diseases: familial Mediterranean fever, hyper-immunoglobulinemia D, TNF-receptor-associated periodic syndrome (TRAPS) and Muckle Wells syndrome. It presents with prolonged attacks of fever and severe localized inflammation. TRAPS is caused by dominantly inherited mutations in the gene encoding the first TNF receptor, which result in decreased serum levels of soluble TNF-receptor leading to inflammation due to unopposed TNF-α action. Corticosteroid treatment is not completely effective in most TRAPS patients. Preliminary experiences with recombinant TNF-receptor analogues in the treatment appear be promising.

Evidence for control of tumour necrosis factor-alpha (TNF-alpha) activity by TNF receptors in patients with proliferative diabetic retinopathy.

TNF-alpha has been implicated in the pathogenesis of insulin- dependent diabetes mellitus (IDDM). At present there are no studies linking serum levels of soluble TNF receptors (sTNF-R) to the development of diabetic microvascular complications such as proliferative diabetic retinopathy (PDR), or to the production of TNF-alpha in these patients. We investigated serum levels of sTNF receptors (sTNF-RI and sTNF-RII) in IDDM patients with or without PDR, and related these to the in vitro production of TNF-alpha upon activation of whole blood and isolated mononuclear cells (MNC). We observed higher serum levels of sTNF-RI in IDDM patients with active (range 945-6630 pg/ml; P = 0.029) or quiescent PDR (range 1675-4970 pg/ml; P = 0.00092) than in individuals with IDDM without retinopathy (range 657-2617 pg/ml) or healthy controls (range 710-1819 pg/ml; P = 0.0092 and 0.0023, respectively). Increased serum levels of sTNF-RII were also seen in IDDM patients with active PDR (range 1749-5218 pg/ml; P = 0.034) or quiescent PDR (range 1494-5249 pg/ml; P = 0.0084) when compared with disease controls (range 1259-4210 pg/ml) or healthy subjects (range 1237-4283 pg/ml). Whole blood production of biologically active TNF-alpha was lower in PDR patients than in disease (P = 0.04) and healthy controls (P < 0.005), contrasting with a higher production of TNF-alpha by lipopolysaccharide (LPS)-activated MNC from PDR patients (P = 0.013). Inhibition of TNF-alpha by TNF-R in plasma supernatants of activated blood from PDR patients was demonstrated by increase of TNF-alpha activity in the presence of anti-TNF-RI and anti-TNF-RII antibodies. These observations suggest that abnormalities in TNF-alpha production and control may operate during the development of microvascular complications of diabetes mellitus.

Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men

Obesity is related to cardiovascular disease (CVD) morbidity and mortality, however, the mechanisms for the development of obesity-induced CVD risk remain unclear. Hyperinsulinemia and insulin resistance are considered key components in the metabolic cardiovascular syndrome and as independent risk factors for CVD. Plasma leptin and tumor necrosis factor-alpha (TNF-α), two adipocyte products, are also proposed to be associated with the development of CVD risk. The purpose of this study is to evaluate the association of plasma leptin, soluble TNF receptors (sTNF-R), and insulin levels as possible mediators of the effect of obesity on atherogenic and thrombogenic CVD risk factors among men. From the Health Professionals Follow-up Study (HPFS), we selected 268 men, aged 47–83 years, who were free of CVD, diabetes, and cancer (except non-melanoma skin cancer), and who had provided a fasting blood sample in 1994. We measured plasma insulin and leptin levels by radioimmunoassay and sTNF-R levels by ELISA. Men in the highest quintile of body mass index (BMI, mean=30.5 kg/m 2) were less physically active and had a more adverse cardiovascular lipid and homeostatic profile, as indicated by levels of insulin, triglyceride (TG), tissue plasminogen activator (t-PA) antigen levels, and apolipoprotein A1 (Apo-A1). In a multivariate regression model controlling for age, smoking, alcohol intake, physical activity and diet, BMI was inversely associated with HDL-cholesterol (HDL-C) and Apo-A1 and positively associated with TG, Apo-B and t-PA antigen levels. The associations between BMI and these CVD risk factors were only slightly changed after adjusting for leptin and/or sTNF-R; but were substantially attenuated after controlling for insulin levels. These data suggest that the association between obesity and biological predictors of CVD may be mediated through changes in plasma insulin, rather than leptin or sTNF-R levels. However, plasma leptin may still play a role in CVD through independent effects on lipid metabolism.

T lymphopaenia in relation to body mass index and TNF‐α in human obesity: adequate weight reduction can be corrective

Although individuals with obesity are susceptible to infection, the underlying causes have not been fully identified. To investigate whether obesity affects immunity, we studied subjects with isolated obesity. Thirty-four obese persons from our outpatient obesity clinic and 50 nonobese healthy control subjects were studied. The effects of weight reduction were evaluated in obese subjects on a very-low-energy diet. We examined blastogenic response, lymphocyte subsets, circulatory TNF-alpha, soluble TNF-alpha receptor 1, soluble TNF-alpha receptor 2, and in vitro TNF-alpha production in obesity. Lymphocyte subsets were analysed with flowcytometry. TNF-alpha and soluble TNF receptors levels were assayed using commercially available enzyme-linked immunosorbent assay kits. Blastogenic responses to phytohemagglutinin or concanavalin A of T cells, CD3(+), CD4(+), CD8(+), CD4(+)CD45RO(+), and TCR alpha beta T cells were significantly diminished in obese subjects. Strong negative correlations were observed between TCR alpha beta and body weight and BMI in obese subjects. Circulatory levels of TNF-alpha, soluble TNF-alpha receptors, and in vitro TNF-alpha production were significantly increased compared to nonobese subjects. In obese subjects, there were significant positive correlations between serum levels of TNF-alpha and waist-hip ratio, serum levels of soluble TNF-alpha receptor 1 and body weight, soluble TNF-alpha receptor 2 and BMI, and soluble TNF-alpha receptor 2 and waist-hip ratio. The T cell responses and previously reduced non-CD8 T cell subsets were increased significantly following weight reduction. Our results suggest that subsets of T cell populations and their function may be reduced in human obesity, and that this may be related, at least in part, to the elevated TNF-alpha production. Furthermore, this T cell dysfunction can be recovered by adequate weight reduction.

Early detection of increased tumour necrosis factor alpha (TNFalpha) and soluble TNF receptor protein plasma levels after trauma reveals associations with the clinical course.

The inflammatory response after trauma includes tumour necrosis factor alpha (TNFalpha) as pro-inflammatory cytokine. Furthermore, both soluble TNF receptor proteins (sTNF-R1 and sTNF-R2) were described to influence the post-traumatic inflammatory response and organ dysfunction. From 47 trauma patients, blood samples were obtained at the scene of accident, at hospital admission, after 4 h, 12 h, and 24 h, and daily until day 6. Plasma levels of TNFalpha, sTNFR1 and sTNF-R2 were measured by enzyme immunoassay (EIA) and analysed comparing clinical parameters such as injury scores (ISS, AIS), development of multiple organ dysfunction syndrome (MODS) and/or systemic inflammatory response syndrome (SIRS), and outcome. Significant changes were observed in a time-dependent manner: TNFalpha and soluble TNF receptor levels were elevated compared to values of healthy persons. At 4 h after trauma, TNFalpha and sTNF-R2 showed an increase from initial values, which continued during the entire observation period. Severe trauma led to enhanced sTNF-R1 levels on scene and on hospital admission. Development of SIRS along with elevated sTNF-R1 began on scene and was present on admission, with increased sTNF-R2 from day 1 to day 4. MODS (until day 6) was preceded by increased sTNF-R2 levels on admission and up to 4 h after trauma. Outcome was associated neither with TNFalpha nor with soluble TNF receptor levels. Thus, in trauma patients, early post-traumatic MODS and SIRS coincide with increased levels of TNFalpha and TNF receptor proteins, revealing different, time-dependent changes. Hence, detection of TNFalpha and soluble TNF receptor proteins after trauma should pay regard to the time point of sampling.

Circulating levels of soluble Fas ligand and soluble Fas in patients with chronic obstructive pulmonary disease

Fas- and tumour necrosis factor (TNF) receptor-mediated apoptosis are known to be two principal apoptotic mechanisms in humans. Although there are several distinctions between these two systems, in vitro studies have demonstrated similar hypoxic activation and a functional relationship. Since patients with chronic obstructive pulmonary disease (COPD) show chronic hypoxaemia and the activation of the TNF- α system, we investigated whether these pathophysiological changes influence the Fas–Fas ligand system. We measured the circulating soluble Fas ligand (sFas-L) level, an inducer of apoptosis, and the soluble Fas receptor (sFas) level, an inhibitor of apoptosis, in 34 COPD patients and 35 age-matched healthy controls. In addition, we investigated the relationships between the levels of sFas-L or sFas and clinical variables including the TNF- α system; circulating TNF- α and soluble TNF-receptor (sTNF-Rs: sTNF-R55 and R75) levels, in the COPD patients. Although circulating TNF- α, sTNF-R55 and R75 levels were significantly higher in the COPD patients than in the healthy controls, serum level of sFas-L (Fisher's exact probability test;P=0·26) and plasma level of sFas [COPD patients vs. controls; mean (SD); 3·74 (0·63) vs. 3·67 (0·48) ng/ml;P=0·89) were not increased in the COPD patients. There was no significant correlation between the levels of sFas-L or sFas and clinical variables in COPD patients. These results suggest that the Fas–Fas ligand system does not independently play an important role in the pathophysiology of patients with COPD.

Plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in patients with bulimia nervosa.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine with numerous immunological and metabolic activities. In addition, TNF-alpha can stimulate a variety of physiological, neuroendocrine and behavioural responses of the central nervous system. In experimental animals, TNF-alpha induces changes in physiological and behavioural parameters which have also been observed in eating disorders. The biological activities of TNF-alpha are mediated by two structurally related, but functionally distinct receptors, TNF-RI and TNF-RII. Since injection of TNF-alpha results in increased shedding of TNF-alpha receptors, it is likely that TNF-alpha release is reflected by soluble TNF-receptors (sTNF-Rs) levels. We studied plasma concentrations of TNF-alpha and two sTNF-Rs (sTNF-RI and sTNF-RII) in female patients with bulimia nervosa. Twenty female patients with bulimia nervosa (BN) and 20 age-matched normal women (N) were studied. Plasma TNF-alpha concentrations were measured by enzyme immunoassay kit and plasma concentrations of sTNF-RI and sTNF-RII were measured by enzyme-linked immunosorbent assay. Plasma TNF-alpha concentrations in BN were significantly higher than those in N (4.7+/- 0.5 ng/l vs. 1.6+/-0.1 ng/l; P<0.01). Although no significant difference was observed in plasma sTNF-RI concentrations between the two groups, plasma sTNF-RII concentrations in BN were significantly higher than those in N (2080.0+/-107.5 ng/l vs. 1569.5 +/-84.0 ng/l; P<0.01). Plasma TNF-alpha concentrations were significantly related to plasma sTNF-RI concentrations (r = 0.511, P<0.05) and to plasma sTNF-RII concentrations (r = 0.532, P<0.05) in bulimic patients. However, plasma TNF-alpha concentrations were not related to body fat mass or to bulimic behaviours in these patients. Our present findings suggest that the adipose tissue may not be the immediate source of TNF-alpha in bulimic patients but the increase in plasma TNF-alpha in these patients may be derived from the central nervous system sources. The elevated sTNF-RII may reflect different shedding kinetics compared with sTNF-RI in bulimic patients.

Plasma leptin and soluble TNF-receptors levels in relation to atherogenic and thrombogenic CVD risk factors among us men

Plasma leptin and soluble TNF-receptors levels in relation to atherogenic and thrombogenic CVD risk factors among us men

Effects of Antidepressants on Weight and on the Plasma Levels of Leptin, TNF-α and Soluble TNF Receptors: A Longitudinal Study in Patients Treated with Amitriptyline or Paroxetine

Leptin, tumor necrosis factor-α (TNF-α), and soluble TNF receptors are involved in weight regulation. Antipsychotic agents, such as clozapine, induce weight gain and increase circulating levels of these cytokines. To assess whether obesity-inducing antidepressants have a similar effect, we measured plasma cytokine levels in depressive inpatients during the first six weeks of treatment with tricyclic agents (amitriptyline or nortriptyline, n = 12), with paroxetine (n = 10), or without medication (n = 14). There was an increase in the body mass index at week 6 of treatment with the tricyclics, which was preceded by a significant increase in soluble TNF receptor p75 plasma levels. Circulating levels of leptin were not affected. Paroxetine and drug-free treatment did not affect any of these parameters. We conclude that weight gain induced by psychotropic agents may occur without increased circulating levels of leptin. However, activation of the TNF-α system might be an early and sensitive marker of ensuing weight gain.

Opposing effects of soluble TNF receptor p55 on the biological action of TNF in a colonic epithelial cell line

Background and Aim: In ulcerative colitis (UC), the levels of extracellular soluble TNF receptors (sTNFRs), known TNF antagonists, increase in the serum and in mucosal lesions. We examined the effect of sTNFRs on TNF-induced ICAM-I expression and IL-8 production in a colonic epithelial cell line to ascertain the role of sTNFRs in DC. Methods: Recombinant TNF (10ng/ml) and recombinant sTNFR (1-I,OOOng/ml) were simultaneously added to confluent HT-29 cells. After 24 hours of incubation, the cell surface expression of ICAM-I was analyzed by flow cytometry, and IL-8 production in the medium and concentrations ofTNF in the serum and colonic mucosa of DC patients were measured by enzyme linked immuno solvent assay (ELISA), and concentration of sTNFR in the serum and colonic mucosa was measured by enzyme linked immunological binding assay. Results: When the sTNFRp55/TNF concentration ratio was greater than or equal to 10, sTNFRs significantly suppressed TNF-induced ICAM-I expression and IL-8 production by HT-29 cells. On the other hand, when the sTNFRp55/TNF concentration ratio was between 1/10 and I, sTNFRs significantly increased TNF-induced ICAM·I expression and IL·8 production in HT-29 cells. The sTNFR concentration was significantly higher in the serum and colonic mucosa of patients with active DC than in controls or patients with inactive DC, but the sTNFRp55/TNF concentration ratio in mucosa did not exceed I in any patients with active DC. Conclusions: The results of the present study showed that relatively low concentrations of sTNFRs enhanced the physiological activity of TNF in a colonic epithelial cell line. The sTNFR concentration in DC patients did not exceed this relatively low concentration range, suggesting that the increase in sTNFRs in the mucosa of DC patients works synergistically with TNF to enhance inflammation. Thus, large quantities of sTNFRp55 are necessary to suppress TNF activity, caution should be exercised when administering sTNFRp55 in a clinical setting.

The relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease.

Although circulating tumor necrosis factor (TNF)-alpha levels have been found to be increased in weight-losing patients with chronic obstructive pulmonary disease (COPD), the main causes for this phenomenon remain to be elucidated. Since hypoxia itself can enhance the production of the TNF-alpha in vitro, we studied the relationship between hypoxemia and activities of the TNF-alpha system, including circulating TNF-alpha and soluble TNF-receptors (sTNF-R; sTNF-R55 and -R75) levels, in 27 COPD patients and 15 age-matched healthy controls. The COPD patients showed a significant weight loss (body mass index = 18.1 +/- 2.8 versus 22.8 +/- 2.2 [mean +/- SD] kg/m(2); p < 0.0001. % fat = 16.3 +/- 5.9 versus 24.3 +/- 4.9 %; p < 0.001), and hypoxemia (Pa(O2 )= 62.2 +/- 9.5 versus 88.6 +/- 5.9 mm Hg; p < 0.0001) as compared with the healthy controls. Serum TNF-alpha (6.15 +/- 1.08 versus 5.41 +/- 1.60 pg/ml; p < 0.05) and plasma sTNF-R55 (1.15 +/- 0.49 versus 0.67 +/- 0.13 ng/ml; p < 0.0001) and sTNF-R75 (3.54 +/- 1.16 versus 2.25 +/- 0.43; p < 0.0001) levels were significantly higher in the COPD patients than in the healthy controls. There were inverse correlations between Pa(O(2)) and circulating TNF-alpha and sTNF-R levels in patients with COPD (TNF-alpha; r = -0.426, p = 0.0297; sTNF-R55: r = -0.587, p = 0.0027; sTNF-R75: r = -0.573, p = 0.0035). In addition, we found inverse correlations between sTNF-R levels and % fat in COPD patients (sTNF-R55: r = -0.442, p = 0.0272; sTNF-R75: r = -0. 484, p = 0.0155). TNF-alpha levels correlated well with sTNF-R levels (sTNF-R55: r = 0.488, p = 0.0127; sTNF-R75: r = 0.609, p = 0. 0019). These relationships were not observed in the healthy controls. These data suggest that systemic hypoxemia noted in patients with COPD is associated with activation of the TNF-alpha system in vivo, which may be a factor contributing to the weight loss in patients with the disease.