Soluble TNF Receptor Levels Research Articles

THU0395 Tumour necrosis factor-alpha as a master regulator of inflammation in erdheim-chester disease: Rationale for the successful treatment of two patients with infliximab

BackgroundErdheim-Chester disease (ECD) is a rare form of systemic non-Langerhans histiocytoses of unknown aetiology. IFN-α is the first-line therapy, but its efficacy varies according to sites of disease involvement. When...

Levels of TNF‐α, soluble TNF receptors (sTNFR1, sTNFR2), and cognition in bipolar disorder

Tumor necrosis factor-alpha (TNF-α) may play an important role in bipolar disorder (BD) pathogenesis. There is only one study about a relationship between TNF-α levels and cognitive impairments in BD. The aim of the present study was to see whether TNF-α, soluble P55 TNF receptor (sTNFR1), and soluble P75 TNF receptor (sTNFR2) levels in BD patients are different from controls and to investigate the relationships between the levels of TNF-α, sTNFR1, and sTNFR2 and the cognitive functions in euthymic BD patients and controls. We assessed 54 BD type I patients and 18 controls by using a battery of neuropsychological tests. Serum TNF-α levels were measured using a commercially available enzyme-linked immunosorbent assay, whereas serum sTNFR1 and sTNFR2 levels were measured using a commercially enzyme-amplified sensitivity immunoassay kit. We found that levels of sTNFR1 and sTNFR2 in BD patients were different from controls. No difference was detected between the BD group and the control group for levels of TNF-α. TNF-α level was found to have a negative correlation with the delayed recall in RAVLT. High levels of sTNFR1 and sTNFR2 in euthymic patients showed that it may support that proinflammatory process continues in euthymic period. This is the first study which showed increased sTNFR2 levels in euthymic period, which could be interpreted as a compensatory mechanism and again the first which deals with verbal memory.

Circulating Levels of TNF Receptor II Are Prognostic for Patients with Peripheral T-cell Non–Hodgkin Lymphoma

Peripheral T-cell non-Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs. Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay. Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99-3.14 with P = 0.056]. A protective role of IL-10-1087A, -824T, and -597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII ≥2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92-4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22-5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different. Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs.

Soy Food Intake and Circulating Levels of Inflammatory Markers in Chinese Women

BackgroundSoy and some of its constituents, such as isoflavones, have been shown to affect the inflammatory process in animal studies. The association between soy food intake and inflammatory markers has not been evaluated adequately in humans. ObjectiveOur aim was to evaluate whether higher intake of soy foods was inversely associated with inflammatory markers in 1,005 middle-aged Chinese women. DesignIn this cross-sectional study, dietary intake of soy foods was assessed by a validated food frequency questionnaire and by a 24-hour recall when biospecimens were procured. A general linear model was used to estimate the geometric means of selected inflammatory markers, including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNFα), soluble IL-6 receptor, soluble GP130, soluble TNF receptors 1 and 2, and C-reactive protein, across categories of soy food intake after adjusting for age, lifestyle and dietary factors, and history of infectious or inflammation-related diseases. ResultsWe found that multivariable-adjusted geometric mean concentrations of IL-6 and TNFα were inversely associated with quintiles of soy food intake, with a difference between the highest and lowest quintiles of 25.5% for IL-6 (P for trend=0.008) and 14% for TNFα (P for trend=0.04). Similar inverse associations were found for TNFα (P for trend=0.003), soluble TNF receptor 1 (P for trend=0.01), soluble TNF receptor 2 (P for trend=0.02), IL-1β (P for trend=0.05), and IL-6 (P for trend=0.04) when soy food consumption was assessed by the frequency of consumption in the preceding 24 hours. No significant associations were found for other markers studied. ConclusionsThis study suggests that soy food consumption is related to lower circulating levels of IL-6, TNFα, and soluble TNF receptors 1 and 2 in Chinese women.

Placenta suppresses experimental autoimmune hypophysitis through soluble TNF receptor 1

Pregnancy modulates autoimmune diseases through diverse and still incompletely defined mechanisms, in part operating at the decidua–placenta interface. To assess the immunological contribution of placenta, we administered mouse placental proteins to a mouse model of autoimmune hypophysitis, a disease known to be strongly associated with pregnancy. Emulsified placental proteins suppressed both the cellular and humoral aspects of hypophysitis. Suppression was specific to self antigens and not seen when two foreign antigens, tetanus toxoid or tuberculin purified protein derivative, were used. Proteomic analysis revealed high levels of soluble TNF receptor 1 in placenta, suggesting that blockade of the TNF-α pathway was a mechanism of disease suppression. Placentas derived from mice deficient in TNF receptor 1 lost the ability to suppress hypophysitis. Notably, hypophysitis suppression was seen only when the TNF-α pathway was blocked locally, at the site of immunization, and not systemically. These findings provide evidence that placenta contributes to the immune tolerance of pregnancy by locally inhibiting the TNF-α pathway.

Elevated Levels of Soluble TNF Receptors 1 and 2 Correlate with Plasmodium falciparum Parasitemia in Pregnant Women: Potential Markers for Malaria-Associated Inflammation

Plasmodium falciparum-infected erythrocytes (IEs) sequester in the intervillous space (IVS) of the placenta causing placental malaria (PM), a condition that increases a woman's chances of having a low-birth-weight baby. Because IEs sequester, they frequently are not observed in peripheral blood smears, resulting in women with PM being misdiagnosed and thus not treated. Because sequestered IEs induce inflammation in the IVS, detection of inflammatory mediators in the peripheral blood may provide an approach for diagnosing PM. Two counterregulatory molecules, TNF-αR (TNFR) 1 and TNFR2, modulate the pathological effects of TNF-α. Levels of these soluble TNFRs (sTNFRs) are reported to be elevated in children with severe malaria, but it is unclear if they are increased in the peripheral blood of PM-positive women with asymptomatic infections. In this study, sTNFR levels were measured throughout the course of pregnancy, as well as at delivery, in women with asymptomatic infections and those who remained uninfected. Results showed that both sTNFRs were significantly increased in the peripheral blood of women with asymptomatic malaria (p < 0.0001) and were positively correlated with parasitemia (p < 0.0001 for sTNFR1 and p = 0.0046 for sTNFR2). Importantly, levels of sTNFR2 were elevated in the peripheral blood of women who were PM-positive but peripheral blood-smear negative (p = 0.0017). Additionally, sTNFR2 levels were elevated in the blood of malaria-positive women who delivered low-birth-weight babies. In vitro studies demonstrated that syncytiotrophoblasts were not a major source of sTNFR. These data suggest that sTNFR2 may be a valuable biomarker for detection of malaria-associated inflammation.

Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder

Bipolar disorder (BD) has been associated with a proinflammatory state in which TNF-α seems to play a relevant role. The aim of the present study was to evaluate the plasma levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in BD patients in mania and euthymia in comparison with control subjects. We evaluated 53 BD patients (34 in mania and 19 in euthymia) and 38 healthy subjects. All subjects were assessed by the Mini-International Neuropsychiatry Interview (MINI-Plus). Patients were also evaluated by the Young Mania Rating Scale (YMRS) and by Hamilton Depression Rating Scale (HDRS). Plasma TNF-α and its soluble receptors were measured by ELISA. The plasma TNF-α and sTNFR2 levels did not differ between groups, but higher sTNFR1 levels were found in BD patients. Of note, BD patients in mania had higher sTNFR1 levels than BD patients in euthymia and controls. The sTNFR1 and sTNFR2 levels correlated with BD duration, and sTNFR2 levels correlated with age of patients. Our data indicate a proinflammatory status in BD patients during mania and further suggest that inflammatory mechanisms may be involved with the physiopathology of BD.

Placental extract suppresses mouse models of autoimmunity (83.4)

Abstract Pregnancy is known to modulate many autoimmune diseases. For example, autoimmune thyroiditis improves during pregnancy, and autoimmune hypophysitis presents during this period. The mechanisms underlying the effect of pregnancy on autoimmunity remain unknown. To determine whether placental proteins influence autoimmunity, we used a mouse model of experimental autoimmune hypophysitis (EAH). Here we report that co-immunization of mice with placental extract and pituitary extract, significantly decreased EAH incidence, severity, and antibody titers. Disease suppression was specific to the placenta; liver or muscle extracts were incapable of suppressing disease. Disease suppression, however, was not specific to EAH: co-immunization of placental extract with thyroglobulin, similarly decreased antibody titers. Immunization with pituitary extract during early or late pregnancy and administration of non-emulsified placental extracts were ineffective in suppressing EAH. Suppression of EAH was only observed when the placental extract was at the same location as the immunogen. Placental extracts were found to contain high levels of soluble TNF receptor one (sTNFR1). Furthermore, a placental extract deficient in TNFR1 was incapable of suppressing EAH, suggesting that sTNFR1 may be responsible for the placental-mediated suppression of EAH. These results suggest that a placental component, possibly sTNFR1, is capable of dampening the immune response to a co-injected immunogen.

Plasma levels of tumor necrosis factor-α and its receptors in patients with mitral stenosis and sinus rhythm undergoing percutaneous balloon valvuloplasty

This study aimed to determine whether plasma levels of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptor (sTNF-R) increases in rheumatic mitral stenosis (MS) patients with sinus rhythm and to examine the effect of percutaneous mitral balloon valvuloplasty (PMBV) on these parameters. Twenty-six patients with MS and sinus rhythm (study group, 20 female, mean age 33 +/- 8 years), who were scheduled for PMBV, and a well-matched control group consisting of 21 healthy volunteers (15 female, mean age 35 +/- 6 years) were enrolled in the study. Tumor necrosis factor-alpha and sTNF-R levels were compared between study patients and controls, and between peripheral and left atrium (LA) blood. Changes in TNF alpha and sTNF-R levels 24 h and 4 weeks after PMBV were analyzed. Significantly higher baseline TNF-alpha and sTNF-R levels were noted in the study group. In the study group, TNF-alpha and its receptors were also found to be higher in LA blood than in baseline peripheral blood. After PMBV, mitral valve area (MVA) increased and transmitral pressure gradient decreased significantly. At the 24th hour after PMBV, the TNF-alpha level decreased from 29.61 +/- 12.22 pg/ml to 22.42 +/- 8.81 pg/ml (P < 0.0001) and at the 4th week, from 22.42 +/- 8.81 pg/ml to 18.92 +/- 7.37 pg/ml (P < 0.0001). Similar reductions were observed in the sTNF-R level. Regression analysis between the difference in sTNF-R level measured 24 h after and before PMBV and the difference in MVA measured 24 h after and before PMBV showed a significant direct relationship between these variables. This study suggests that isolated rheumatic MS without atrial fibrillation is accompanied by increased TNF-alpha and sTNF-R level. The successful PMBV establishes a significant reduction in TNF-alpha and its receptors, probably due to improved postprocedural hemodynamic parameters.

Resistance to mycobacterial infection: A pattern of early immune responses leads to a better control of pulmonary infection in C57BL/6 compared with BALB/c mice

In this study, we have compared the immunological responses associated with early pulmonary mycobacterial infection in two mouse strains, BALB/c and C57BL/6 known to exhibit distinct differences in susceptibility to infection with several pathogens. We infected mice via the intranasal route. We have demonstrated that BALB/c was less able to control mycobacterial growth in the lungs during the early phase of pulmonary infection. Our results showed that during the early phase (day 3 to week 1), BALB/c mice exhibited a delay in the production of TNF and IFN-γ in the lungs compared to C57BL/6 mice. Levels of IL-12 and soluble TNF receptors (sTNFR) were comparable between the mouse strains. The cellular subset distribution in these mice before and after infection showed a higher increase in CD11b+ cells in the lungs of C57BL/6, compared to BALB/c as early as day 3 postinfection. At early time points, higher levels of monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein 1 (MIP)-α were detected in C57BL/6 than BALB/c mice. In vitro, BCG-infected bone marrow derived macrophages (BMM) from both mouse strains displayed similar capacities to either phagocytose bacteria or produce soluble mediators such as TNF, IL-12 and nitric oxide (NO). Although IFN-γ stimulation of infected BMM in both mouse strains resulted in the induction of antimycobacterial activity, BALB/c mice had a reduced capacity to kill ingested bacteria. The above observations indicate that the chain of early, possibly innate immunological events occurring during pulmonary mycobacterial infection may directly impact on increased susceptibility or resistance to infection.

Neuroimmunotrophic regulation in vascular dementia: Serum TNF-alpha and IGF-I

Background and aims: Experimental data suggest that the signaling pathways of tumor necrosis factor alpha (TNF-alpha) and insulin-like growth factor I (IGF-I) are functionally interrelated and might be relevant for the brain pathology of AD and vascular dementia (VaD). Recently we reported enhanced TNF-alpha levels, reduced IGF-I concentrations and a negative correlation between free IGF-I and TNF-alpha values in the serum of AD patients. Increased levels of soluble TNF Receptor I (sTNF-RI) and IGF binding protein 3 (IGFBP-3), both having pro-apoptotic activity, have also been found in AD sera.

Infliximab Reduces the Cytokine-Mediated Inflammation but Does Not Suppress Cellular Infiltration of the Vessel Wall in Refractory Kawasaki Disease

The aim of our study was to evaluate the efficacy of infliximab for the treatment of patients with refractory Kawasaki disease (KD) and investigate the dynamic changes of cytokines during infliximab treatment. We have performed a study of cytokine and proinflammatory molecule levels in 43 KD patients including 18 responders to IVIG, 14 nonresponders, and 11 patients treated with infliximab. We determined serum levels of soluble TNF receptor I (sTNFR I) and IL-6, as well as VEGF, damage associated molecular pattern (DAMP) molecules; myeloid-related protein (MRP)8/MRP14 and S100A12 sequentially. In eight patients, fever subsided immediately upon infliximab treatment. Four patients, who started infliximab after 12 d of illness, developed coronary artery lesions. Each of the cytokines was elevated before infliximab treatment in all patients. Although serum levels of proinflammatory cytokines decreased dramatically after infliximab treatment, DAMP molecules and VEGF and markers of local tissue damage were not suppressed. In contrast, in IVIG responders all cytokines decreased markedly after IVIG treatment. We show that infliximab is one of the adoptive therapies in refractory KD patients. Different behaviors of proinflammatory cytokines and DAMP molecules and VEGF after infliximab treatment suggest that infliximab is effective for suppression of cytokine-mediated inflammation, but could not completely block local vasculitis.

CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscle

CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on ASM CD40 and OX40L expression. CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-alpha and/or IFN-gamma was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. Interferon-gamma and TNF-alpha synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-gamma reduced TNF-alpha-induced OX40L expression to a similar extent in both cell types. TNF-alpha and IFN-gamma induced CD40 via nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-kappaB and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-kappaB, but these were not statistically significant. The reduced OX40L expression with TNF-alpha and IFN-gamma involved extracellular regulated kinase 1/2 activation. Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-gamma may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression.

PLACENTA SUPPRESSES DISEASE IN EXPERIMENTAL AUTOIMMUNE HYPOPHYSITIS AND THYROIDITIS

To determine whether placental proteins influence autoimmunity, we employed two mouse models of endocrine diseases that are affected differently by pregnancy: experimental autoimmune thyroiditis and hypophysitis. In the hypophysitis model, addition of mouse placenta to the immunogen, mouse pituitary, decreased both disease incidence and severity (p = 0.02). This decrease was accompanied by a significant decline in total IgG (p &lt; 0.001) and IgG1 titers (p = 0.014). Similar results were obtained when three different concentrations of placenta were used. Disease suppression was specific to the placenta; addition of mouse liver or muscle to the immunogen was incapable of suppressing disease (p = 0.80). In the thyroiditis model, addition of mouse placenta to a different immunogen, thyroglobulin, similarly decreased disease incidence (p = 0.002) and severity. Mouse placenta contained significantly higher levels of soluble TNF receptor one (sTNFR1) when compared by cytokine array to a skeletal muscle control. We therefore tested by ELISA whether serum sTNFR1 levels related to disease but found no correlation. These results suggest that a placenta factor is capable of dampening the immune response to a co‐injected immunogen and if identified could serve as a potential therapeutic.

The Expression of Inflammatory Mediators and its Association with the Susceptibility to Mucosal Leishmaniasis in Peru (136.6)

Abstract Leishmania braziliensis can cause cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) in humans, and the latter is characterized by excessive T- and B-cell responses. We hypothesized that conversion from CL to ML is partially due to an imbalanced production of proinflammatory and regulatory cytokines, leading to uncontrolled host responses to the parasites. To test this hypothesis, we first examined the -2518 SNP of the MCP-1 promoter because its G/G genotype is associated with autoimmune disorders and infectious diseases. We genotyped 142 Peruvian subjects (18 controls, 65 CL and 59 ML patients) using PCR-RFLP on genomic DNA. Our pilot studies suggested that ML patients showed a relatively frequency for the MCP-1 G/G genotype (28/62, 45%) than the A/A (9/22, 41%) or A/G genotypes (2/58, 38%), respectively. Using dot blot analysis, we detected higher levels of MCP-1, IFN-γ, IL-8, IP10, MIP-1β, -1d, and soluble TNF receptors in the sera of CL and ML patients as compared with the healthy controls. Additional quantitative studies confirmed that sera of ML patients contained significantly higher levels of IP-10, MIP-1β and sTNFRII when compared to CL and healthy controls. This study suggests that the over-production of inflammatory cytokines is a contributing factor to the pathogenesis of mucosal lesions. Studies are ongoing to define the sources of these inflammatory mediators.

Serum levels of sTNF-R1, sTNF-R2 and CXCL9 correlate with disease activity in adult type paracoccidioidomycosis

Paracoccidioidomycosis (PCM) is the most common systemic mycosis in Latin America. A major problem in the management of PCM is to determine the best time to discontinue therapy due to the high relapse rate among patients. Soluble TNF receptors (sTNF-R) levels and chemokines are associated with disease activity in several infectious, inflammatory and autoimmune disorders. The aim of the present work was to evaluate levels of sTNF-R1, sTNF-R2 and chemokines in serum of patients with adult type of PCM, before and after antifungal therapy, and to correlate those levels to disease activity. Concentrations of sTNF-R1, sTNF-R2 and CXCL9 were higher in untreated patients and decreased progressively with treatment. The serum marker with the best accuracy to discriminate PCM cases from controls was sTNF-R2. sTNF-R1 did not drop to control levels before 36 months of treatment. CCL2 and CCL3 levels were low at baseline in PCM patients, raised significantly after 12 months of treatment and diminished thereafter. CCL24 levels were higher after 36 months of antifungal therapy in PCM patients. CCL11 levels were not statistically different from control subjects. sTNF-R1, sTNF-R2 and CXCL9 may be useful as laboratory parameters to assess disease activity in PCM patients.

Effect of Infliximab on Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease: A Pilot Study

Background: Chronic obstructive pulmonary disease (COPD) with cachexia is characterized by inflammation reflected by increased levels of tumor necrosis factor-α (TNF-α). Objectives: In this study, infliximab, an anti-TNF-α antibody, was evaluated for its effects on systemic (plasma) and local (exhaled breath condensate, EBC) inflammation in cachectic patients with COPD. Also, baseline levels of new inflammatory markers were compared to control subjects. Methods: Sixteen cachectic patients with moderate to severe COPD were examined for inflammatory status at baseline and compared to 25 control subjects. Patients were randomized (1:1) to receive infliximab (5 mg/kg) or placebo at weeks 0, 2 and 6. Patients were evaluated at weeks 8 and 12 and followed through week 26. Results: EBC analysis revealed increased levels of several novel inflammatory markers, including macrophage migration inhibitory factor, IL-12, RANTES and sICAM-1, in patients with COPD compared to controls. EBC levels of inflammatory markers were unchanged in patients receiving infliximab. In addition, systemic levels of acute-phase proteins (C-reactive protein, fibrinogen and lipopolysaccharide-binding protein), IL-6 and soluble TNF receptor (sTNFR) 55 had not changed at weeks 8 or 12. Small increases in circulating levels of sTNFR75, myeloperoxidase and Clara cell protein 16 were seen at week 8, but not at week 12. Conclusions: In this small study, infliximab did not produce an observable decrease in local inflammation in cachectic patients with COPD and had minor effects on systemic inflammation. The detection of new inflammatory markers in EBC can help to further characterize local inflammatory processes in COPD.

Changes in HLA-DR expression, cytokine production and coagulation following endotoxin infusion in healthy human volunteers

The infusion of a low dose of endotoxin into healthy subjects triggers a complex inflammatory response but the intricacies of which, despite extensive research, are still being unraveled. Nine healthy male volunteers received a dose of 30 Units endotoxin/kg bodyweight as an intravenous bolus. Following endotoxin infusion the concentration of TNF-alpha in their serum rapidly increased within 30 min, peaked after 1–2 h and returned to baseline by 4 h. This corresponded to a similarly rapid increase in anti-inflammatory soluble TNF receptor (sTNFR) levels, which remained elevated for up to 48 h. Increased levels of other cytokines were measured, including IL-6, IL-8, G-CSF, IL-1ra and IL-10. However, these cytokines lagged behind that of TNF-alpha and remained elevated for up to 8 h. Endotoxin injection resulted in complex changes in HLA-DR expression, a marker of monocyte activation state. Initially, following a lag of 2–4 h, HLA-DR expression decreased with a nadir at 8 h, followed by an increase in expression above baseline at 22 h. HLA-DR levels returned to baseline 48 h post-endotoxin challenge. This was in contrast to endotoxin-induced changes in white blood cell (WBC) numbers, which dropped rapidly (at 2–3 h) while HLA-DR levels were stable and then peaked during the nadir in HLA-DR expression (8 h). Furthermore, endotoxin injection caused activation of both fibrinolytic and coagulation pathways. Thus, endotoxin infusion results in complex changes in HLA-DR expression, production of pro- and anti-inflammatory cytokines and activation of coagulation.

Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes

Clear evidence exists that TNF-alpha inhibits insulin signalling and thereby glucose uptake in myocytes and adipocytes. However, conflicting results exist with regard to the role of TNF-alpha in type 2 diabetes. We obtained blood and biopsy samples from skeletal muscle and subcutaneous adipose tissue in patients with type 2 diabetes (n = 96) and healthy controls matched for age, sex and BMI (n = 103). Patients with type 2 diabetes had higher plasma levels of fasting insulin (p < 0.0001) and glucose (p < 0.0001) compared with controls, but there was no difference between groups with regard to fat mass. Plasma levels of TNF-alpha (p = 0.0009) and soluble TNF receptor 2 (sTNFR2; p = 0.002) were elevated in diabetic patients. Insulin sensitivity was correlated with quartiles of plasma TNF-alpha after adjustment for age, sex, obesity, WHR, neutrophils, IL-6 and maximum O(2) uptake (VO2/kg) in the diabetes group (p < 0.05). The TNF mRNA content of adipose or muscle tissue did not differ between the groups, whereas muscle TNF-alpha protein content, evaluated by western blotting, was higher in type 2 diabetic patients. Immunohistochemistry revealed more TNF-alpha protein in type 2 than in type 1 muscle fibres. After adjustment for multiple confounders, plasma TNF-alpha is associated with insulin resistance. This supports the idea that TNF-alpha plays a significant role in the pathogenesis of chronic insulin resistance in humans. However, findings on the TNF-alpha protein levels in plasma and skeletal muscle indicate that measurement of TNF mRNA content in adipose or muscle tissue provides no information with regard to the degree of insulin resistance.

TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population.

The cytokines tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors p55 and p75, and interleukin 6 (IL-6) are involved in host defense against several microbiological agents, in the process of inflammation and also in body weight regulation. In the present study, we sought to assess the influence of age, gender, smoking, and body mass index on plasma levels of TNF-alpha, TNF receptors, and IL-6 in more than 550 adult subjects randomly selected from the Bavarian population. None of the cytokine parameters had a normal distribution and all distributions were significantly skewed. The cytokine plasma levels investigated increased significantly with age, while gender had a relatively weaker influence on the plasma levels. Plasma levels of TNF-alpha, TNF receptors, and IL-6 correlated significantly with the BMI. The study provides insights into factors influencing the cytokine levels investigated in a randomly chosen study sample.