Serum sTNF-RI Research Articles

Association of Baseline Serum Soluble Tumour Necrosis Factor Receptor Levels with the Response of Rheumatoid Arthritis to Janus Kinase Inhibitor Therapy.

The aim of this study was to investigate whether cytokines associated with tumour necrosis factor- (TNF-) α and interleukin- (IL-) 6 signalling could predict rheumatoid arthritis (RA) clinical remission (CR) with Janus kinase inhibitor (JAKinib) treatment using the Simplified Disease Activity Index (SDAI). Eighty-nine patients with RA treated with JAKinibs were enrolled, and their clinical data were collected retrospectively. CR was defined as an SDAI ≤ 3.3 after 6 months of treatment with JAKinib. The serum samples of 89 patients were analysed for IL-6, soluble IL-6 receptor (sIL-6R), soluble gp130 (spg130), and soluble TNF receptor- (sTNFR-) I and sTNFR-II titres. There were no significant differences in the baseline clinical parameters between the CR and non-CR groups. Serum levels of IL-6, sIL-6R, and sgp130 were not significantly different; whereas, the serum sTNFR-I and sTNFR-II levels were significantly lower in the CR group. Univariate and multivariate logistic regression analysis showed that the baseline log sTNFR II values (OR: 0.002; p = 0.034) were predictors of CR. Patients with RA can be stratified prior to JAKinib administration using serum sTNFR-I and sTNFR-II levels but not serum IL-6 axis cytokine levels (IL-6, sIL-6R, and sgp130).

Increased Serum Levels of Soluble TNF-α Receptor Is Associated With ICU Mortality in COVID-19 Patients.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected over 112M patients and resulted in almost 2.5M deaths worldwide. The major clinical feature of severe COVID-19 patients requiring ventilation is acute respiratory distress syndrome (ARDS) possibly associated with a cytokine storm.ObjectivesTo elucidate serum levels of TNF-α and soluble TNF-Receptor 1 (sTNFR1) in patients with severe and mild COVID-19 disease as determinants of disease severity.MethodsWe determined serum TNF-α and sTNFR1 concentrations in 46 patients with laboratory-confirmed COVID-19 (17 patients with severe disease within the intensive care unit [ICU] and 29 non-severe, non-ICU patients) and 15 healthy controls upon admission using ELISA. Subjects were recruited between March-May 2020 at the Masih Daneshvari Hospital Tehran, Iran.ResultsSerum levels of sTNFRI were significantly higher in ICU patients (P<0.0001) and non-ICU patients (P=0.0342) compared with healthy subjects. Serum sTNFR1 were significantly higher in ICU patients than in non-ICU patients (P<0.0001). Serum TNF-α levels were greater in ICU and non-ICU patients than in the healthy subjects group (p<0.0001). The sTNFRI concentration in ICU (r=0.79, p=0.0002) and non-ICU (r=0.42, p=0.02) patients positively correlated with age although serum sTNFRI levels in ICU patients were significantly higher than in older healthy subjects. The sTNFRI concentration in ICU patients negatively correlated with ESR.ConclusionsThe study demonstrates higher sTNFRI in ICU patients with severe COVID-19 disease and this be a biomarker of disease severity and mortality. Future studies should examine whether lower levels of systemic sTNFR1 at admission may indicate a better disease outcome.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

Characteristic elevation of soluble TNF receptor II : I ratio in macrophage activation syndrome with systemic juvenile idiopathic arthritis.

To investigate the clinical significance of soluble tumour necrosis factor receptor (sTNF-R) II/I ratio as an indicator of the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA), we measured the serum sTNF-RI and II levels in 117 patients with s-JIA, including 29 patients with MAS, 15 with Epstein-Barr virus-induced haemophagocytic lymphohistiocytosis (EBV-HLH), 15 with Kawasaki disease (KD) and 28 healthy controls (HCs). We determined their correlation with measurements of disease activity and severity. Furthermore, we measured serum interleukin (IL)-18 levels in patients with EBV-HLH and compared these in levels in patients with MAS. The sTNF-RII/I ratio was elevated significantly in MAS and EBV-HLH patients compared with those in the acute phase of s-JIA and KD patients, whereas there were no significant differences between HCs and those in the acute phase of s-JIA. The sTNF-RII/I ratio increased profoundly as MAS developed and correlated positively with disease activity. Serum IL-18 levels were elevated significantly in MAS patients compared with EBV-HLH patients. The monitoring of serum IL-18 and sTNF-RII/I might be useful for the diagnosis of MAS and the differentiation between MAS and EBV-HLH.

Serum ferritin as an indicator of the development of encephalopathy in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome

To investigate the diagnostic value of serum ferritin levels as a marker of disease activity and the development of encephalopathy in hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli. Twenty patients with HUS were studied. Serum ferritin levels were compared with clinical features and serum soluble tumor necrosis factor receptor (sTNFR) I and sTNFRII levels. Serum sTNFRI and sTNFRII levels were quantified by enzyme-linked immunosorbent assays. Serum ferritin levels were significantly elevated at the time of the diagnosis of HUS. Serum ferritin levels were significantly elevated in patients with encephalopathy compared to patients without encephalopathy. HUS patients with serum ferritin levels of >687.5ng/ml were at high risk of encephalopathy. Serum ferritin levels were significantly positively correlated with serum sTNFRI and sTNFRII levels. Serum ferritin levels are a promising indicator of the development of encephalopathy in HUS.

Age- and gender-dependent changes in circulating concentrations of tumor necrosis factor-α, soluble tumor necrosis factor receptor-1 and sulfated glycosaminoglycan in healthy people

In this study, the effect of gender and physiological ageing on circulating concentrations of plasma sulfated glycosaminoglycans (sGAG) as well as molecules involved in pro- (tumor necrosis factor-α; TNF-α) and anti-inflammatory responses (soluble tumor necrosis factor receptor-1, sTNF-RI) were assessed. The relationships between sGAG and molecules involved in age-dependent extracellular matrix (ECM) remodeling during physiological ageing were also investigated. Circulating TNF-α and sTNF-RI were measured in 91 healthy volunteers using enzyme-linked immunosorbent assays. sGAG were quantified using an Alcian blue-binding assay. A linear age-related decline in plasma sGAG was found during the first five decades of life (r=-0.61, p<0.05), followed by an increase occurring only in females (r=0.46, p<0.05). Circulating TNF-α concentrations were inversely correlated with age (r=-0.24, p<0.05) over the lifetime. For TNF-α, the observed changes were gender specific. Serum sTNF-RI concentrations were not affected by age in either men or women. A significant positive correlation was found between the concentrations of TNF-α and both sGAG (r=0.22, p<0.05) and sTNF-RI (r=0.21, p<0.05). Our data demonstrate that physiological ageing is associated with ECM remodeling, reflected by plasma sGAGs concentrations. Changes in the ECM metabolism during the ageing process were influenced by circulating TNF-α. Furthermore, serum concentrations of biomolecules involved in pro- and anti-inflammatory responses are not increased in healthy elderly subjects.

Serum soluble tumour necrosis factor receptor type I concentrations independently predict prognosis in patients with breast cancer

The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer. The following circulating cytokines were measured in 210 histopathologically confirmed, untreated breast cancer patients: interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The patients have been followed-up for 10 years. bFGF and VEGF showed the highest diagnostic sensitivity. Only IL-6 concentrations were related to the clinical stage. A high percentage of patients in clinical stage I showed increased serum sTNF RII, VEGF and bFGF concentrations, of which only sTNF RII was found to be increased in a smaller percentage of patients with more advanced disease compared with patients with early stage disease. Patients aged 50 years and more presented with significantly higher concentrations of sTNF RI, IL-10, IL-6 and VEGF compared with younger patients. In multivariate analysis, a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer. Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.

Association between polymorphisms in tumor necrosis factor (TNF) and TNF receptor genes and circulating TNF, soluble TNF receptor levels, and bone mineral density in postmenopausal Korean women

The aim of the present study was to investigate the relationship of polymorphisms in the tumor necrosis factor (TNF)-alpha, TNF-beta, and TNF receptor (TNFR) genes to circulating TNF, soluble TNFR (sTNFR) levels, and bone mineral density (BMD) in women. The TNF-alpha G(-308)A, C(-857)T, C(-863)A, T(-1031)C, TNF-beta A252G, TNFRI A36G, TNFRII T676G, A1663G, A1668G, and C1690T polymorphisms were analyzed in 377 postmenopausal Korean women. The levels of serum TNF-alpha, TNF-beta, sTNFRI, sTNFRII, and bone turnover markers were measured. BMD was examined by dual energy x-ray absorptiometry. After adjustment for age, body mass index, and years since menopause, no significant differences in BMD of the lumbar spine and femoral neck and serum levels of bone turnover markers were detected, according to single polymorphisms in TNF and TNFR genes and combined polymorphisms. However, the frequencies of the TT genotype of TNF-alpha T(-1031)C polymorphism, the non-AA genotype of TNF-beta A252G polymorphism, and the GG genotype of TNFRII A1663G polymorphism were significantly higher in osteoporotic women than in women with normal BMD, respectively (P < 0.05). The TNFRII T676G polymorphism affected the serum sTNFRI and sTNFRII levels. The serum sTNFRII levels in the CC genotype of TNFRII C1690T polymorphism were the highest, with a G or C allele dose effect, and the TNFRII G676C/C1690T haplotype genotype also affected serum sTNFRII levels. TNF-alpha T(-1031)C, TNF-beta A252G, and TNFRII A1663G polymorphisms may be genetic factors for osteoporosis in Korean postmenopausal women, and the TNFRII T676G and C1690T polymorphisms and their combined polymorphism affected serum sTNFRII levels. The TNFRII T676G polymorphism also affected the serum sTNFRI levels.

Changes of cytokines in cirrhosis patients with advanced hepatocellular carcinoma treated by intra-arterial chemotherapy

Tumor necrosis factor (TNF) induces cancer cell-specific apoptosis by binding to a TNF-related apoptosis-inducing ligand. Binding of the Fas ligand on cytotoxic T lymphocytes to the Fas receptor on hepatocytes is also known to induce apoptosis. The aim of this study was to clarify changes of cytokines in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) receiving intra-arterial combination chemotherapy. Twenty-one adult Japanese LC patients with aHCC received intra-arterial combination chemotherapy. The serum levels of TNF-alpha, soluble TNF receptor-I (sTNFr-I), soluble Fas ligand (sFas L), and soluble Fas (sFas) were evaluated. Thirteen of the 21 patients (group R) showed an objective response, while the other eight patients (group N) showed no response. The serum level of TNF-alpha was lower after chemotherapy than before chemotherapy in group N, but there was no difference of serum sTNFr-I levels between before and after chemotherapy and there were also no differences between the two groups. The serum sFas levels were higher after chemotherapy than before chemotherapy in group N, while there was no difference among groups. These results indicate that a high serum TNF-alpha level and a low serum sFas level might be important for successful combined arterial chemotherapy in LC patients with aHCC.

High serum TNF-α level in Type 2 diabetic patients with microangiopathy is associated with eNOS down-regulation and apoptosis in endothelial cells

A high dose of tumor necrosis factor (TNF)-α induces endothelial dysfunction and enhances apoptosis in vitro. The present study was conducted to examine whether incubating human umbilical vein endothelial cells (HUVECs) with serum from Type 2 diabetic patients complicated with retinopathy and/or microalbuminemia demonstrate endothelial dysfunction. Serum levels of TNF-α and vascular endothelial growth factor (VEGF) were elevated in diabetic patients. Plasma levels of TNF-α, two soluble TNF-α receptors (sTNFR), and VEGF were assessed in diabetic patients (CD, n=21) complicated with retinopathy and/or nephropathy, uncomplicated diabetic patients (UD, n=18), and in healthy normal participants (NS, n=16). In HUVECs incubated with patient's serum, endothelial constitutive nitric oxide synthase (eNOS) protein expressions were measured by Western blot analysis. Apoptosis in HUVECs was determined by optical microscopy, DNA fragmentation, and CPP32-like protease activity. Serum TNF-α, sTNFR-I, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, in CD were significantly higher than in UD or NS. While, serum sTNFR-I and VEGF levels were significantly increased in the both diabetic patients, compared with those of NS, no difference was observed in the serum TNF-α, sTNFR-II, and ADMA levels between UD and NS. eNOS down-regulation and apoptosis were seen in HUVECs incubated with serum from CD for 24 h, but those observations were completely counteracted in the incubation by the addition of the antihuman TNF-α antibody. These results imply that eNOS down-regulation in CD is associated with high serum TNF-α levels despite of high serum of VEGF levels. Therefore, endothelial dysfunction in diabetic patients complicated with microangiopathy may, in part, be attributed to high serum TNF-α levels.

Equivalence of the Acute Cytokine Surge and Myocardial Injury after Coronary Artery Bypass Grafting with and without a Novel Extracorporeal Circulation System

Cardiopulmonary bypass (CPB) contributes to a morbidity-inducing systemic inflammatory response after cardiac surgery. We compared this response in patients receiving coronary artery bypass grafting (CABG) with (CPB group; n = 7) or without (off-pump group; n = 8) the Minimal Extracorporeal Circulation (MECC) system. Serum concentrations of tumour necrosis factor (TNF)-alpha, soluble TNF receptors, pro- and anti-inflammatory interleukins (ILs) and other myocardial injury markers were measured after anaesthetic induction, at 1 h, 4 h and 24 h after completing all anastomoses or serially. Soluble TNF receptor type I (sTNFRI) and IL-8 peaked early after CABG in both groups and did not decline. Serum sTNFRI was significantly higher in the CPB compared with the off-pump group at 1 h, whereas IL-8 was significantly lower in the CPB group throughout. The MECC system, therefore, produces an equivalent acute cytokine response and degree of myocardial injury to off-pump CABG, and may be useful when CABG cannot be performed without CPB.

Increased serum soluble tumor necrosis factor receptor levels are associated with insulin resistance in liver cirrhosis

Insulin resistance is present in nearly all patients with liver cirrhosis, but its etiology remains unclear. Recent studies have shown that tumor necrosis factor-α (TNF-α) system is involved in the insulin resistance of human obesity. Serum concentrations of TNF-α, and 2 soluble TNF receptors (sTNF-RI and sTNF-RII) are increased in cirrhotic patients. This study explored whether TNF-α system activity was associated with insulin resistance in liver cirrhosis. A total of 26 male nondiabetic patients with liver cirrhosis (mean age, 59 ± 3 years; body mass index, 23.7 ± 0.4 kg/m 2) and 25 male control subjects (age, 65 ± 2 years; body mass index, 24.4 ± 0.5 kg/m 2) were studied. Serum insulin, c-peptide, TNF-α, sTNF-RI, and sTNF-RII concentrations were determined by immunoassay. The insulin resistance was estimated by homeostasis assessment model (HOMA IR). In cirrhotic patients, serum levels of TNF-α, sTNF-RI, and sTNF-RII were all higher than those in the controls, and correlated with disease severity. Also, the serum c-peptide, insulin concentrations, and the HOMA IR were higher in liver cirrhosis with comparable blood glucose to control subjects, indicating a degree of insulin insensitivity. In the whole population, there was a moderate, but statistically significant, correlation between serum sTNF-RI or sTNF-RII, and HOMA IR. Also, body mass index was associated with HOMA IR, but not related to serum TNF-α, and sTNF-Rs levels. In multiple regression analysis, both sTNF-RII and body mass index jointly contributed to 30% variance of HOMA IR. Our study demonstrated that elevated sTNF-RII levels were associated with insulin resistance in liver cirrhosis. The data indicated that TNF-α system might play a role in modulating insulin action in patients with liver cirrhosis.

Elevation of serum soluble tumour necrosis factor (TNF) receptor and IL-1 receptor antagonist levels in bronchial asthma.

The specific inhibitor for TNF-alpha activity, soluble form of the 55-kD TNF receptor (sTNF-RI) and soluble form of the 75-kD receptor (sTNF-RII), and the specific inhibitor for IL-1 activity, IL-1 receptor antagonist (IL-1Ra), have been identified. It has been shown that the levels of these inhibitors are elevated in plasma/serum and biological fluids in several diseases, and the protective and inhibitory effect of these inhibitors exist in several inflammatory diseases. In the present study, we measured serum levels of sTNF-RI, STNF-RII and IL-1Ra by ELISA in 36 patients with bronchial asthma (16 atopic and 20 non-atopic) during asthma attacks and in stable conditions in order to assess the state of these inhibitors in allergic inflammation. The levels of sTNF-RI, sTNF-RII and IL-1Ra in sera obtained during bronchial asthma attacks were higher than those in sera obtained in stable conditions. These findings were obtained regardless of atopic status. These results suggest that higher levels of serum sTNF-RI, sTNF-RII and IL-1Ra may reflect up-regulation of TNF-R expression and IL-1Ra production in allergic inflammation, and sTNF-RI, sTNF-RII and IL-1Ra may contribute to regulating TNF-alpha- and IL-1-mediated production and development of allergic inflammation.

Increased serum leptin concentrations correlate with soluble tumour necrosis factor receptor levels in patients with cirrhosis.

Several reports have documented the involvement of hyerleptinaemia in malnutrition associated with liver cirrhosis. However, the mechanisms of elevated leptin levels remains unclear. Serum concentrations of tumour necrosis factor-alpha (TNF-alpha), and two soluble TNF receptors (sTNF-RI and sTNF-RII) are increased in patients with liver cirrhosis. In rodents, administration of TNF-alpha has been shown to stimulate plasma leptin concentration, suggesting that a cytokine-leptin link may mediate anorexia and weight loss during chronic inflammation. In this study, we investigate the potential interaction of the TNF-alpha system with leptin in the development of malnutrition in liver cirrhosis. A total of 26 male patients with liver cirrhosis and 25 healthy people were recruited at an outpatient clinic at the Veterans General Hospital in Taiwan. Serum biochemistry and anthropometric measurement by bioelectrical impedance analysis were used to assess nutrition status, and immunoassay was used to determine serum leptin, TNF-alpha sTNF-RI and sTNF-RII concentrations. In cirrhotic patients, the body fat mass (FM) and serum albumin levels were both lower than control subjects [15.8 (13.2-19.5) kg vs. 18.9 (16.2-20.1) kg; 35 (33-41) g/l vs. 43 (41-45) g/l, respectively; P < 0.05]. Serum TNF-alpha sTNF-RI and sTNF-RII were significantly elevated in cirrhotic patients compared to healthy controls [9.8 (7.2-13.5) ng/l vs. 4.3 (3.4-7.3) ng/l; 1682.1 (1344.8-2179.4) ng/l vs. 1319.6 (1037.7-1632.1) ng/l; 4462.2 (3748.5-5159.4) ng/l vs. 3559.8 (2506.9-3988.9 ng/l, respectively; P < 0.01] and correlated with disease severity (graded by Pugh-Child's scores). An inverse correlation was observed between circulating sTNF-RI and sTNF-RII to serum albumin levels (r =-0.42, r = -0.398; P < 0.05). The serum leptin levels in cirrhotic patients were significantly higher [6.0 (3.6-7.7) (g/l vs. 3.4 (2.9-4.3) (g/l; P < 0.01) and correlated with body FM (r = 0.52; P < 0.01]. Using a multiple linear regression analysis with leptin as dependent variable and FM and TNF-alpha, sTNF-R as independent variables, FM and serum sTNF-RI concentrations were found to predict independently the leptin levels in cirrhotic patients. Our study demonstrated that serum levels of TNF-alpha, sTNF-RI, sTNF-RII and leptin were all elevated in cirrhotic patients. The severity of liver cirrhosis was an important factor for the activation of TNF-alpha system. The activated TNF-alpha system conjointly with hyperleptinaemia might mediate malnutrition in patients with liver cirrhosis.

Tuberculosis (TB) and HIV infection are independently associated with elevated serum concentrations of tumour necrosis factor receptor type 1 and beta2-microglobulin, respectively.

The aim of this study was to identify immune markers that are independently associated with HIV infection or TB in vivo. Using commercially available assays, we measured concentrations of five immune markers in sera from 175 out-patients attending medical clinics in Cote D'Ivoire and Ghana, West Africa. Patients were categorized into groups with TB only (TB+HIV-, n = 55), TB and HIV co-infection (TB+HIV+, n = 50), HIV infection only (TB-HIV+, n = 35), or neither infection (TB-HIV-, n = 35). TB+HIV+ and TB-HIV+ groups were matched for blood CD4+ lymphocyte count. Mean +/- s.d. concentrations of beta2-microglobulin were similarly increased in both the TB-HIV+ (5.3+/-2.1 microg/ml, P<0.0001) and the TB+HIV+ (5.0+/-1.5 microg/ml, P<0.0001) groups compared with the TB-HIV- group (2.2+/-1.8 microg/ml), but were only slightly increased in the TB+HIV- group (3.2+/-1.8 microg/ml, P = 0.01). In contrast, mean serum concentrations of soluble tumour necrosis factor receptor type I (sTNF-RI) were similarly elevated in the TB+HIV- (1873+/-799 pg/ml, P<0.0001) and TB+HIV+ (1797+/-571 pg/ml, P<0.0001) groups compared with uninfected subjects (906+/-613 pg/ml), but there was only a small increase in sTNF-RI in the TB-HIV+ group (1231+/-165 pg/ml, P = 0.03). Both TB and HIV infection were associated with substantial elevation of serum concentrations of soluble CD8, soluble CD54, and sTNF-R type II. Analysis of additional samples from groups of TB+HIV- and TB+HIV+ patients receiving anti-TB treatment showed significant and equal reductions in mean serum sTNF-RI concentrations, but no significant change in mean beta2-microglobulin. Thus, serum beta2-microglobulin and sTNF-RI serve as relatively independent markers of HIV infection and TB, respectively, in studies of co-infected persons.

Polymethylmethacrylate efficacy in reduction of renal itching in hemodialysis patients: crossover study and role of tumor necrosis factor-alpha.

Pruritus is one of the major unsolved problems for patients receiving regular hemodialysis. In this study, we conducted a 6 month prospective and crossover trial to investigate the effect of polymethylmethacrylate (PMMA) membrane for renal itching. We also examined the role of the tumor necrosis factor (TNF)-alpha system for pruritus in hemodialysis patients. We assessed the degree of skin itching and measured circulating levels of TNF-alpha and soluble TNF receptors (sTNFR-I, sTNFR-II) in 19 patients using hemodialysis, complicated by prolonged severe pruritus for 6 months. Serum sTNFR-I and II levels were significantly elevated in hemodialysis patients compared to normal subjects. Serum sTNFR-II levels were significantly and negatively correlated with serum albumin (r = -0.602, p = 0.007). A significant positive relationship was also found between sTNFR-I and erythropoietin dosage (r = 0.554, p = 0.016). However, no association was found between the degree of pruritus and circulating sTNFR-I and II values. Skin itching scale was significantly decreased from 2.7 +/- 0.2 to 2.1 +/- 0.3 following the use of PMMA membrane for 3 months (p < 0.05). In contrast, there was no change in itching scales during 3 months of conventional therapy (2.2 +/- 0.3 versus 2.2 +/- 0.3, p = NS). PMMA itself did not affect serum TNF-alpha and sTNFR values as well as conventional dialyzer membranes. These findings suggested that the PMMA dialyzer can improve renal itching not mediated through the modification of the TNF-alpha system.

TNF-alpha expression in painful and nonpainful neuropathies.

To determine whether the cytokine tumor necrosis factor alpha (TNF-alpha) acts as a pain mediator in neuropathic pain in humans. In animal models, inflammatory cytokines such as TNF-alpha have been shown to facilitate neuropathic pain. The expression of TNF-alpha was analyzed immunohistochemically in 20 human nerve biopsy specimens of patients with painful (n = 10) and nonpainful (n = 10) neuropathies. Additionally, serum soluble TNF-alpha receptor I (sTNF-RI) levels were determined in 24 patients with neuropathies, 16 of which were painful and 8 that were painless. Colocalization studies by confocal fluorescence microscopy for S-100 and TNF-alpha showed expression of TNF-alpha in human Schwann cells. Patients with painful neuropathies showed a stronger TNF-alpha immunoreactivity in myelinating Schwann cells relative to the epineurial background staining compared with patients with nonpainful neuropathy (0.949 +/- 0.047 vs 1.010 +/- 0.053, p < 0.05). Although there was no difference in sTNF-RI levels between painful (n = 16) and nonpainful (n = 8) neuropathies (sTNF-RI: 1412 +/- 545 pg/mL vs 1,318 +/- 175 pg/mL), patients with a mechanical allodynia (n = 9) had elevated serum sTNF-RI (1627 +/- 645 pg/mL vs 1233 +/- 192 pg/mL, p < 0.05) compared with patients without allodynia (n = 15). TNF-alpha expression of human Schwann cells may be up-regulated in painful neuropathies. The elevation of sTNF-RI in patients with centrally mediated mechanical allodynia suggests that systemic sTNF-RI levels may influence central pain processing mechanisms.

Beryllium-stimulated release of tumor necrosis factor-alpha, interleukin-6, and their soluble receptors in chronic beryllium disease.

Chronic beryllium disease (CBD) provides a model system in which to evaluate the antigen-stimulated, cell-mediated, immune response that leads to granulomatous lung disease. We hypothesized that beryllium salts would stimulate bronchoalveolar lavage (BAL) cell release of tumor necrosis factor-alpha (TNF-alpha) and lnterleukin-6 (IL-6), and their soluble receptors, soluble TNF receptor I (sTNF RI), sTNF RII, and sIL-6R and that chronic exposure to antigen would increase production of soluble receptors in the serum and BAL fluid (BALF) of beryllium-sensitized and CBD patients. We have demonstrated (1) similar constitutive TNF-alpha, IL-6, and soluble receptor production by control subjects and CBD patients, (2) a BeSO4-stimulated increase in TNF-alpha and IL-6 production by CBD-derived BAL cells, and (3) a BeSO4-induced decrease in sTNF RII production by BAL cells from control subjects. We measured increased serum sTNF RI and serum and BALF sIL-6R in beryllium-sensitized subjects and increased sTNF RI and RII in serum and sIL-6R and sTNF RII and BALF in CBD patients. These changes correlated with pulmonary lymphocytosis and clinical measures of disease severity, indicating that soluble receptors may reflect disease status.