sTNFR1 Levels Research Articles

The Neuroimmune and Neurotoxic Fingerprint of Major Neurocognitive Psychosis or Deficit Schizophrenia: a Supervised Machine Learning Study.

No studies have examined the immune fingerprint of major neurocognitive psychosis (MNP) or deficit schizophrenia using M1 macrophage cytokines in combination with chemokines such as CCL2 and CCL11. The present study delineated the neuroimmune fingerprint of MNP by analyzing plasma levels of IL-1β, sIL-1RA, TNFα, sTNFR1, sTNFR2, CCL2, and CCL11 in 120 MNP versus 54 healthy controls in association with neurocognitive scores (as assessed with the Brief Assessment of Cognition in Schizophrenia) and PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. MNP was best predicted by a combination of CCL11, TNFα, IL-1β, and sIL-1RA which yielded a bootstrapped (n = 2000) area under the receiver operating curve of 0.985. Composite scores reflecting M1 macrophage activity and neurotoxic potential including effects of CCL11 and CCL2 were significantly increased in MNP. A large part of the variance in PHEM (38.4-52.6%) and negative (65.8-74.4%) symptoms were explained by combinations of immune markers whereby CCL11 was the most important. The same markers explained a large part of the variance in the Mini-Mental State examination, list learning, digit sequencing task, category instances, controlled word association, symbol coding, and Tower of London. Partial least squares analysis showed that 72.7% of the variance in overall severity of schizophrenia was explained by the regression on IL-1β, sIL-1RA, CCL11, TNFα, and education. It is concluded that the combination of the abovementioned markers defines MNP as a distinct neuroimmune disorder and that increased immune neurotoxicity determines memory and executive impairments and PHEMN symptoms as well.

Plasma inflammatory biomarkers and modifiable lifestyle factors associated with colorectal cancer risk.

Chronic inflammation is a leading cause of colorectal cancer (CRC). Inflammatory biomarkers are considered indicators of occult malignancy. To contribute to the investigation of CRC prevention strategies, we aimed to identify associations between inflammatory biomarkers (insulin-like growth factor-1 (IGF-1), soluble tumor necrosis factor receptor 2 (sTNFR-2), and interleukin-8 (IL-8)) and modifiable lifestyle factors including body mass index (BMI), prior BMI, smoking status, alcohol consumption status, physical activity, and dietary inflammatory index (DII) score in terms of CRC risk. In a hospital-based case-control study, we explored the associations of plasma IGF-1, sTNFR-2, and IL-8 levels with CRC risk in 697 cases and 1845 controls. Unconditional logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for CRC with the inflammatory biomarkers adjusted for confounders. CRC patients had significantly higher levels of sTNFR-2 and IL-8 than the controls (P<0.001). In multivariate models, the levels of IGF-1, sTNFR-2, and IL-8 were significantly associated with CRC risk after adjusting for confounders (IGF-1 OR (95% CI)=1.39 (1.02-1.89), P for trend=0.018; sTNFR-2=2.14 (1.59-2.90), P for trend<0.001; IL-8=1.95 (1.43-2.66), P for trend<0.001, highest vs. lowest quartiles). The biomarkers showed either positive or negative trends when modifiable lifestyle factors were stratified. In particular, the inverse associations of CRC risk with the biomarkers were significant among subjects who engaged in regular physical activity and had an anti-inflammatory diet pattern. Elevated levels of inflammatory biomarkers were associated with CRC risk and could be modified by risk and protective lifestyle factors. Our findings may provide a strategy to identify CRC risk based on the associations between inflammatory biomarkers and lifestyle factors.

Serum Levels of Selected Cytokines in B-Cell Precursor Acute Lymphoblastic Leukemia and Their Association with Prognostic Factors and Survival

Introduction: Dysregulated production of cytokines has been implicated in the onset and progression of various types of cancer. Better understanding of leukemia microenvironment is essential for development of new treatment approaches. The aim of this study was to evaluate serum levels of selected cytokines in B-cell precursor acute lymphoblastic leukemia (B-ALL) at diagnosis and in complete remission (CR), and their association with acknowledged prognostic factors, relapse-free survival (RFS) and overall survival (OS). Methods: A total of 42 de novo B-ALL patients (median age 49, range 19-75 years; 28 males, 14 females; all Caucasian) were included in this study. Nineteen patients were BCR/ABL positive. Serum samples were taken at diagnosis and in CR. We used Cytokine IV Array (manufactured by Randox Laboratories Ltd., Crumlin, UK) containing the following analytes: soluble receptor α for IL-2 (sIL-2Rα), soluble receptor for IL-6 (sIL-6R), soluble receptor for TNF-α type I (sTNFR-1), soluble receptor for TNF-α type II (sTNFR-2) and Matrix Metalloproteinase-9 (MMP-9). All analytes were measured by biochip array technology on Evidence Investigator analyzer. Correlations between cytokines, acknowledged prognostic factors (age, WBC count, immunophenotype, BCR/ABL, response to induction therapy), RFS and OS were evaluated separately in both clinical situations. Statistical evaluation was done by a professional statistician using software R 3.5.3 (R Core Team 2019). Probability values (p)&lt;0.05 with Bonferroni-Holm correction were considered statistically significant. Results: At diagnosis of B-ALL, we found significantly higher levels of sIL-2Rα, sIL-6R, sTNFR-1, sTNFR-2 and significantly lower levels MMP-9 in comparison with CR (p&lt;0.001 in all cases). Levels of sTNFR-1 correlated with sTNFR-2 at diagnosis and in CR (p&lt;0.001). In CR, sIL-2Rα correlated with sIL-6R, sTNFR-1, TNFR-2 (p&lt;0.001) and sIL-6R correlated with sTNFR-2 (p&lt;0.001). BCR/ABL positive patients had higher levels of sIL-2Rα at diagnosis (r=0.484; p=0.014), but not in CR. Correlations of cytokines with other acknowledged prognostic factors in B-ALL did not reach statistical significance. In our cohort, CR after 1 cycle of induction therapy was achieved in 88 % of patients, 1-year RFS was 74 % and 1-year OS was 86 %. Serum levels of evaluated cytokines were not associated with achievement of CR after 1 cycle of induction therapy, RFS or OS. Conclusions: Cytokines are an important part of leukemia microenvironment. Our results show that serum levels of all evaluated cytokines are significantly altered in newly diagnosed B-ALL, reflecting activity of the disease. We found statistically significant correlation between BCR/ABL positivity and sIL-2Rα levels at diagnosis. So far, we did not find any significant correlations with response to induction therapy, RFS or OS. Further studies with a larger spectrum of cytokines and a longer follow-up will be needed. Disclosures No relevant conflicts of interest to declare.

Systemic inflammation in COPD in relation to smoking status

&#x0D; &#x0D; &#x0D; Background and aims: Smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) that has been recently defined as a systemic pul- monary inflammatory disease. However, the impact of smok- ing itself on systemic inflammation in COPD patients has not yet been well established. The aim of our study was to inves- tigate the association between inflammatory markers and smoking status.&#x0D; Material and methods: We compared 202 current smokers, 61 ex-smokers and 57 never-smokers, all COPD patients. Assessments included medical history, spirometry, alpha-1 antitrypsin (AAT) genotyping, serum AAT, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and soluble tumor necrosis factor receptor (sTNFR)-1 and sTNFR-2 concentra- tions.&#x0D; Results: AAT and CRP concentrations in smokers (1.75 ± 0.51 g/L and 14.4 [9.5–20.5] mg/L) and ex-smokers (1.69 ± 0.43 g/L and 12.3 [8.7–16.3] mg/L) were higher than in never-smokers (1.49 ± 0.38 g/L and 5.1 [2.5–8.7] mg/L; p &lt; 0.05). sTNFR-1 level was higher in smokers than ex-smokers or never-smok- ers (241.2 pg/mL [145.3–349.4] vs. 213.7 pg/mL [147.1– 280.3] and 205.2 pg/mL [125–275]; p &lt; 0.05).&#x0D; Conclusions: Our data confirm that smoking is associated with increased levels of AAT, CRP, and sTNFR-1 in COPD patients, an array of systemic inflammation markers that continue to be active even after smoking cessation.&#x0D; &#x0D; &#x0D;

P826Peri-procedural treatment with high dose Rosuvastatin reduces soluble TNF receptor 1 in patients treated with primary percutaneous coronary intervention for ST elevation myocardial infarction

Abstract Background The extent of cardiac injury in ST elevation myocardial infarction (STEMI) depends on the level of inflammation and subsequent immune cell recruitment. An inflammatory phase that is disproportionately prolonged, of excessive magnitude, or insufficiently suppressed, can lead to sustained tissue damage and improper healing, promoting infarct expansion, adverse remodelling and chamber dilatation. Soluble TNF receptor 1 (sTNFR-1) is believed to mirror systemic pan-inflammatory status more closely than a single cytokine antigenic level. sTNFR-1 levels might give prognostic information, independent from and, at the same time, additive with some well-recognized outcome predictors such as left ventricular ejection fraction. Purpose We hypothesised that sTNFR-1 and other inflammatory markers could be modulated by statins. Methods Plasma levels of inflammatory markers were measured at baseline, 2 days, 7 days and 2 months in consecutive patients with first time STEMI with single vessel disease. Twenty-five patients (treatment group (TG)) were treated with 80 mg Rosuvastatin daily with first dose before primary percutaneous coronary intervention (PCI) whereas the control group (CG) consisted of 34 patients in whom treatment with 20 mg simvastatin daily were initiated the day after PPCI. Results sTNFR1 increased during the first 48 hours following PCI and this increase was larger in the CG compared with the TG (0.22±0.30 ng/mL vs 0.08±0.19 ng/nmL, p=0.025). The difference in increase during one week was only borderline statistically significant (0.21±0.30 ng/mL vs 0.08±0.26 ng/mL, p=0.081). These differences in the kinetics of sTNRF-1 were mirrored by changes in Pentraxin 3 (PTX3) between groups from baseline to 1 week, CG vs TG. (0.28±0.70 μmol/l vs 0.10±0.05 ng/mL, p=0.014) and at 2 months (−0.42±0.56 ng/mL vs 0.08±0.60 μmol/l, p=0.032) Conclusion High dose Rosuvastatin therapy initiated peri-procedural during PPCI for STEMI reduces pan inflammation as reflected by sTNFR1 and is associated with a less abrupt fall in PTX3 at 1 week and 2 months supporting recent research suggesting that PTX3 plays a cardiovascular protective effect in cardiovascular disease and healing. Acknowledgement/Funding Western Norway Regional Health Authority

Tumor necrosis factor alpha (TNF-α) and its soluble receptors are associated with disability, disability progression and clinical forms of multiple sclerosis.

The association between tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1 and sTNFR2 with clinical characteristics of multiple sclerosis (MS) remains unclear. To examine whether TNF-α, sTNFR1 and sTNFR2 are associated with MS diagnosis, disability, disability progression and clinical forms of MS. The study included 147 patients with relapsing-remitting MS (RRMS), 21 with progressive clinical forms (ProgMS) and 70 controls. Expanded Disability Status Scale (EDSS) evaluated disability as mild (EDSS < 3.0) or moderate/high (EDSS ≥ 3.0). Multiple Sclerosis Severity Score (MSSS) evaluated disability progression as no progression (MSSS < 5) and progression (MSSS ≥ 5). Baseline data of subjects and plasma levels of TNF-α, sTNFR1, sTNFR2 were obtained. The MS diagnosis explained 44.6% and 12.3% of TNF-α and sTNFR2 levels, respectively. Moderate/high disability and disability progression were best predicted by sTNFR1 and age (positively) and ProgMS were best predicted by sTNFR1 (positively) and sTNFR2 (negatively), coupled with age and sex. A composite score reflecting the sTNFR1/sTNFR2 ratio showed a positive association with ProgMS after adjusting for age and sex. Increased sTNFR1 and age were positively associated with disability and disability progression, whereas increased sTNFR1 (positively) and sTNFR2 (negatively) were associated with ProgMS, suggesting a distinct role of them in the immunopathological mechanisms of MS.

Ligands and receptors of the TNF superfamily are decreased in major depression and during early antidepressant therapy

BackgroundThe up-regulation of pro-inflammatory agents, amongst them tumor necrosis factor (TNF), may represent low-grade inflammation in major depression. To further elucidate inflammatory mechanisms related to TNF in depression, the aim of the current study was to investigate the involvement of ligands and receptors of the TNF/TNF-receptor-superfamily yet un- or little explored in major depression. MethodsSerum levels of ligands (TNF, TNF-related weak inducer of apoptosis [TWEAK], B-cell activating factor [BAFF], tumor necrosis factor superfamily member 14 [TNFSF14; LIGHT], A proliferation-inducing ligand [APRIL]) and receptor molecules (TNF receptor superfamily member 8 [TNFRSF8; sCD30], soluble TNF receptor type 1 [sTNFR1] and type 2 [sTNFR2]) of the TNF/TNF-receptor-superfamily were measured in 50 unmedicated patients suffering from major depression and 48 healthy controls and were reassessed in 37 of the depressed patients two weeks after the initiation of antidepressive treatment. ResultsIn comparison to the healthy controls, the interrelated serum levels of TWEAK, BAFF, TNFSF8, sTNFR1 and sTNFR2 were reduced both in the unmedicated and medicated depressed patients. Serum levels of BAFF and TNF significantly increased during the initiation of antidepressive treatment. In the combined sample of unmedicated depressed and healthy controls, but not the separate groups, scores of the BDI-II inversely correlated with levels of TWEAK, BAFF, sTNFR1, sTNFR2 and TNFSF8. ConclusionThe current findings give evidence for a role of the TNF/TNF-receptor-superfamily in the pathophysiology of major depression that may involve reduced tissue regeneration and neurogenesis rather than an acceleration of pro-inflammatory pathways.

Interplay of TNF-α, soluble TNF receptors and oxidative stress in coronary chronic total occlusion of the oldest patients with coronary heart disease

BackgroundThe interplay of tumour necrosis factor-α (TNF-α) and oxidative stress was related to severities of coronary atherosclerosis and congestive heart failure. We tried to identify TNF-α, soluble tumour necrosis factor-α receptor-1 (sTNFR-1), soluble tumour necrosis factor-α receptor-2 (sTNFR-2) and oxidative stress as potential non-invasive diagnostic and therapeutic biomarkers for coronary chronic total occlusion (CCTO) in the oldest patients with coronary heart disease (CHD). MethodsWe determined the expression levels of TNF-α, sTNFR-1, sTNFR-2, oxidative stress biomarkers (malondialdehyde [MDA], aldosterone [ALD], angiotensin II [Ang II], and high sensitivity C-reactive protein [hs-CRP]) in oldest patients with CCTO. ResultsThe levels of TNF-α, sTNFR-1, sTNFR-2, MDA, ALD, Ang II and hs-CRP were increased in oldest patients with CCTO (P < 0.001). The CCTO of oldest patients with CHD may involve the interplay of TNF-α, sTNFR-1, sTNFR-2 and oxidative stress. ConclusionsThe TNF-α, sTNFR-1, sTNFR-2 and oxidative stress could be considered as potential non-invasive diagnostic and therapeutic biomarkers for CCTO in the oldest patients with CHD.

Inflammation time-axis in aseptic loosening of total knee arthroplasty: A preliminary study.

ObjectiveAseptic loosening (AL) is the most frequent long-term reason for revision of total knee arthroplasty (TKA) affecting about 15–20% patients within 20 years after the surgery. Although there is a solid body of evidence about the crucial role of inflammation in the AL pathogenesis, scared information on inflammation signature and its time-axis in tissues around TKA exists.DesignThe inflammation protein signatures in pseudosynovial tissues collected at revision surgery from patients with AL (AL, n = 12) and those with no clinical/radiographic signs of AL (non-AL, n = 9) were investigated by Proximity Extension Assay (PEA)-Immunoassay and immunohistochemistry.ResultsAL tissues had elevated levels of TNF-family members sTNFR2, TNFSF14, sFasL, sBAFF, cytokines/chemokines IL8, CCL2, IL1RA/IL36, sIL6R, and growth factors sAREG, CSF1, comparing to non-AL. High interindividual variability in protein levels was evident particularly in non-AL. Levels of sTNFR2, sBAFF, IL8, sIL6R, and MPO discriminated between AL and non-AL and were associated with the time from index surgery, suggesting the cumulative character of inflammatory osteolytic response to prosthetic byproducts. The source of elevated inflammatory molecules was macrophages and multinucleated osteoclast-like cells in AL and histiocytes and osteoclast-like cells in non-AL tissues, respectively. All proteins were present in higher levels in osteoclast-like cells than in macrophages.ConclusionsOur study revealed a differential inflammation signature between AL and non-AL stages of TKA. It also highlighted the unique patient’s response to TKA in non-AL stages. Further confirmation of our preliminary results on a larger cohort is needed. Analysis of the time-axis of processes ongoing around TKA implantation may help to understand the mechanisms driving periprosthetic bone resorption needed for diagnostic/preventative strategies.

Pretransplant Levels of C-Reactive Protein, Soluble TNF Receptor-1, and CD38+HLADR+ CD8 T Cells Predict Risk of Allograft Rejection in HIV+ Kidney Transplant Recipients

IntroductionHIV-positive (HIV+) kidney transplant recipients exhibit a 2- to 3-fold increased risk of allograft rejection. Dysregulated immune activation in HIV infection persists despite successful antiretroviral therapy and is associated with non-AIDS morbidity, including renal disease. We hypothesized that the pathological levels of inflammation and immune activation associated with chronic HIV infection could have clinical utility in the prediction of rejection in HIV+ kidney recipients.MethodsProspective cohort study of 22 HIV-negative (HIV−; donor) to HIV+ (recipient) kidney transplant recipients who underwent biomarker assessment pretransplant and were subsequently followed for development of acute rejection. Plasma levels of markers of inflammation (soluble tumor necrosis factor receptor 1 [sTNF-R1] and C-reactive protein [CRP]) and microbial translocation (soluble CD14 and lipopolysaccharide) were measured by enzyme-linked immunosorbent assay or chromogenic endpoint assay. Levels of activated (CD38+HLADR+) CD4+ and CD8+ T cells, and T regulatory cells (CD4+CD25highFoxP3+) were measured by flow cytometry.ResultsAmong the biomarkers evaluated, only the pretransplant levels of sTNF-R1, CRP, and frequencies of CD38+HLADR+ CD8 T cells, were found to be at significantly higher levels among patients who experienced biopsy-proven acute rejection. Confirming our hypothesis, patients with high pretransplant levels of sTNF-R1 or activated CD8+ T cells had a significantly increased 200-day cumulative incidence of biopsy-proven acute rejection (0 vs. 38% for both; P = 0.01). Similarly, pretransplant CRP levels higher than 5 μg/ml were associated with increased risk of acute rejection within the first 6 months post-transplant (0 vs. 43%; P = 0.01).ConclusionBiomarker-based identification of HIV+ recipients at increased risk for rejection might facilitate individualized induction immunosuppression regimens in this vulnerable patient population.

Inflammation and breast density among female Chinese immigrants: exploring variations across neighborhoods.

We examined associations of inflammation with breast density, a marker of breast cancer risk, among female Chinese immigrants and explored whether associations varied by neighborhood environment. Assessments of serum C-reactive protein (CRP), soluble tumor necrosis factor receptor 2 (sTNFR2), and breast density were performed among 401 Chinese immigrants across the Philadelphia region. Participant addresses were geocoded, with the majority residing in areas representing traditional urban enclaves (i.e., Chinatown and South Philadelphia) or an emerging enclave with a smaller, but rapidly growing Chinese immigrant population (i.e., the Near Northeast). The remainder was classified as residing in non-enclaves. In multivariable adjusted regression models, CRP was inversely associated with dense breast area (p = 0.01). Levels of sTNFR2 were also inversely associated with dense breast area, but these associations varied by neighborhood (interaction p = 0.01); specifically, inverse associations were observed among women residing in the emerging enclave (p = 0.03), but not other neighborhoods. Among Chinese immigrant women, aggregate analyses that do not take neighborhood context into consideration can mask potential variations in association of inflammatory markers with breast density. Future studies should consider how neighborhood contextual factors may contribute to differential risk pathways.

Adipose-derived mesenchymal stem cells ameliorate acute liver injury in rat model of CLP induced-sepsis via sTNFR1

Sepsis is characterized as exceed inflammation response and multiple organs dysfunction. Many articles suggested that mesenchymal stem cells can alleviate the inflammation and improve the survival rate of inflammatory animal models, however, the mechanism is still unclear. This study aimed to test the hypothesis that rat adipose-derived mesenchymal stem cells (ADMSCs) produce a amount of soluble tumour necrosis factor receptor 1 (sTNFR1), which ameliorated liver injury and inflammation and increased the survival rate of septic rat model.120 adult male Sprague-Dawley rats were randomly divided into 4 groups: sham-operated (Sham), sepsis-induced by cecal ligation and puncture (CLP), shNC (injected 1 × 106 ADMSCs with transfected with scramble shRNA 1 h after CLP), and shsTNFR1 (injected 1 × 106 ADMSCs with transfected with sTNFR1 1 h after CLP). The serum sTNFR1 levels were the lowest in Sham and highest in shNC group. ADMSCs could decrease the levels of pro-inflammatory cytokines such as TNF-α, IL-6, AP-1 c-jun and NF-κB p56 after CLP administration, whereas this result was weaken by shsTNFR1 administration. Moreover, shNC had an increased levels of the anti-inflammatory factor IL-10 compared with CLP, and this change could be weakened in shsTNFR1 administration. More importantly, ADMSCs could improve the survival rate of CLP-induced septic rats. Therapeutically administered ADMSCs secrete sTNFR1, which alleviated the liver injury and inflammatory response. Additionally, ADMSCs also ameliorated the systematic inflammation and increased the survival rate of septic rats.

Tumor Necrosis Factor-alpha, TNFR, And STNFR Relationships to Body Temperature

PURPOSE: To examine the TNF-α, TNFR, and STNFR relationships to body temperature in response to in the heat. METHODS: 12 recreationally active men (24.4 ± 3.1 yrs; 181.0 ± 6.8 cm; 81.5 ± 8.0 kg; 47.2 ± 4.8 ml·kg−1·min−1) completed an exercise protocol under four conditions: 23°C/45%RH; 23°C/70%RH; 35°C/20%; and 35°C/45% RH. The protocol consisted of a 60-minute cycling trial at 60% VO2max, a 15-minute rest, and a time-to-exhaustion trial at 90% VO2max (TTE). Blood was collected before (T1) and after (T2) the 60-minute trial, and immediately after TTE (T3). Plasma concentrations of TNF-α, STNFR1, and STNFR2 were measured via ELISA. Surface expression of TNFR1 and TNFR2 on human classical (CD14++CD16–) monocytes was measured via flow cytometry (n=8). Participant’s rectal (Tre) and skin temperatures at 5 locations: Chest, Triceps, Forearm, Thigh and Calf were monitored continuously. Total skin temperature (Tsk) and whole body temperature (Twb) were calculated using weighted averages. The Area Under the Curve with respect to increase (AUCi) was then calculated for Tre, Tsk and Twb. Data were analyzed as Pearson Product Moment Correlations between AUCi for Tre, Tsk and Twb with TNF-α, TNFR, and STNFR. The time spent above specific critical temperatures for Tre (37.5, 38.0, 38.5 and 39.0°C) and Twb (35.0, 36.0, 37.0 and 38.0°C) were related to TNF-α, TNFR, and STNFR using stepwise linear regression. RESULTS: Tre was correlated with the change in STNFR1 from T1 to T3 (r= 0.307; p=0.048) and with the change in STNFR2 from T1 to T3 (r= 0.340; p=0.028). Tsk was correlated with both the change in STNFR1 from T1 to T2 (r= 0.321; p=0.038) and from T1 to T3 (r= 0.320; p=0.039); with the change in STNFR2 from T1 to T3 (r= 0.430; p=0.004); and with the change in TNF-α from T1 to T2 (r= 0.357; p=0.020). Time spent with a Tre above 38.5°C was related to the change in STNFR1 from both T1 to T2 (r= 0.837; p<0.001) and from T1 to T3 (r= 0.773; p<0.001); and to the change in TNF-α from T1 to T2 (r= 0.426; p=0.005) and from T1 to T3 (r= 0.415; p=0.006). CONCLUSION: Changes in circulating levels of TNF-α, STNFR1, and STNFR2 are influenced by rectal and whole body temperature. Classical monocyte expression of TNFR1 and TNFR2 do not appear to be influenced by rectal or whole body temperature. This investigation was partially funded by Kent State University Research Council.

Interference of tumor necrosis factor inhibitor treatments on soluble tumor necrosis factor receptor 2 levels in rheumatoid arthritis

ObjectiveSoluble Tumor Necrosis Factor Receptor II (sTNFR2) is used as a biomarker to study cardiovascular disease (CVD) in diverse populations. TNF inhibitors (TNFi's) are a common treatment for inflammatory conditions. The objective of this study was to examine whether TNFi use impacts measured sTNFR2 levels. MethodsWe studied blood samples from a cohort of RA patients with clinical data and high sensitivity-C-reactive protein (hsCRP) measurements. To assess for interference, we tested the entire cohort for the expected positive correlation between sTNFR2 and TNFi using Pearson correlations. We then performed Pearson correlations between sTNFR2 and TNFi and sequentially removed subjects on adalimumab, etanercept, and infliximab; if interference was occurring, no correlation would be observed between hsCRP and sTNFR2, and correlation would be restored by removing subjects on the treatment causing the interference. ResultsWe studied 190 subjects, 84.2% female, 73.4% anti-CCP positive. All subjects with sTNFR2 level exceeding measurable level were on etanercept. The expected positive correlation between hsCRP and sTNFR2 was not observed when assessing the entire cohort, r = 0.05, p = 0.51. However, the expected correlation was restored only after excluding subjects on etanercept, r = 0.46, p < 0.0001, and not adalimumab or infliximab. ELISA for sTNFR2 was performed using etanercept only and demonstrated direct binding to sTNFR2. ConclusionsOur data identified interference between etanercept and the TNFR2 assay. Of the TNFi's, only etanercept has a TNF-binding domain modeled after TNFR2. These data should be considered when designing studies using sTNFR2 in populations where etanercept is a treatment option.

Soluble TNF-R1, VEGF and other cytokines as markers of disease activity in systemic lupus erythematosus and lupus nephritis.

Current non-invasive methods of assessing disease activity in systemic lupus erythematosus (SLE) are of limited sensitivity and specificity. Testing includes acute phase markers, autoantibodies and complement levels. Although measurements of dsDNA antibodies and complement C3/C4 levels are routine, they remain of limited value. Improved blood and urine markers may help in early detection of flare, distinction between flare and chronic damage, and monitoring response to therapy. A total of 87 patients with SLE were tested for the following cytokines in serum and urine: monocyte chemoattractant protein 1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), soluble tumour necrosis factor receptor 1 (sTNF-R1), interferon-inducible protein 10 (IP-10), monocyte inhibitory protein 1α (MIP-1α) and vascular endothelial growth factor (VEGF). Patients attending the Lupus Unit at St Thomas' Hospital, London, UK were divided into active lupus nephritis (LN), inactive LN and non-renal SLE groups based on their renal pathology and SLE disease activity index (SLEDAI). Cytokine testing was performed using the FIDIS multiplex bead assay. The mean level of serum sTNF-R1 was higher in the active LN group compared with both inactive LN and non-renal SLE groups ( p < 0.001). For urine measurements there were significant differences between active LN and non-renal SLE for VEGF ( p = 0.016), after statistical correction for multiple testing. Both urinary and serum sTNF-R1 and IP-10 levels correlated with SLEDAI scores ( p < 0.001), while serum VEGF correlated weakly with SLEDAI ( p = 0.025). The optimum combination for differentiating active from inactive LN patients was serum VEGF, sTNF-R1, MCP-1 and glomerular filtration rate plus urinary sTNF-R1 and protein-creatinine ratio. These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for VEGF in the urine. This study has confirmed the ability of the multiplex bead technique to detect cytokines in a good analytical range, including very low and high levels, in both serum and urine. Combining serum and urine markers provided additional sensitivity in distinguishing active from inactive LN.

Identification of inflammatory and vascular markers associated with mild cognitive impairment.

Biochemical processes have been associated with the pathogenesis of mild cognitive impairment (MCI) and dementia, including chronic inflammation, dysregulation of membrane lipids and disruption of neurotransmitter pathways. However, research investigating biomarkers of these processes in MCI remained sparse and inconsistent. To collect fresh evidence, we evaluated the performance of several potential markers in a cohort of 57 MCI patients and 57 cognitively healthy controls. MCI patients showed obviously increased levels of plasma TNF-α (p = 0.045) and C-peptide (p = 0.004) as well as decreased levels of VEGF-A (p = 0.042) and PAI-1 (p = 0.019), compared with controls. In addition, our study detected significant correlations of plasma sTNFR-1 (MCI + Control: B = -6.529, p = 0.020; MCI: B = -9.865, p = 0.011) and sIL-2Rα (MCI + Control: B = -7.010, p = 0.007; MCI: B = -11.834, p = 0.003) levels with MoCA scores in the whole cohort and the MCI group. These findings corroborate the inflammatory and vascular hypothesis for dementia. Future studies are warranted to determine their potential as early biomarkers for cognitive deficits and explore the related mechanisms.

HIV, Cytomegalovirus, and Malaria Infections during Pregnancy Lead to Inflammation and Shifts in Memory B Cell Subsets in Kenyan Neonates.

Infections during pregnancy can expose the fetus to microbial Ags, leading to inflammation that affects B cell development. Prenatal fetal immune priming may have an important role in infant acquisition of pathogen-specific immunity. We examined plasma proinflammatory biomarkers, the proportions of various B cell subsets, and fetal priming to tetanus vaccination in cord blood from human United States and Kenyan neonates. United States neonates had no identified prenatal infectious exposures, whereas Kenyan neonates examined had congenital CMV or mothers with prenatal HIV or Plasmodium falciparum or no identified infectious exposures. Kenyan neonates had higher levels of IP-10, TNF-α, CRP, sCD14, and BAFF than United States neonates. Among the Kenyan groups, neonates with prenatal infections/infectious exposures had higher levels of cord blood IFN-γ, IL-7, sTNFR1, and sTNFR2 compared with neonates with no infectious exposures. Kenyan neonates had greater proportions of activated memory B cells (MBC) compared with United States neonates. Among the Kenyan groups, HIV-exposed neonates had greater proportions of atypical MBC compared with the other groups. Although HIV-exposed neonates had altered MBC subset distributions, detection of tetanus-specific MBC from cord blood, indicative of fetal priming with tetanus vaccine given to pregnant women, was comparable in HIV-exposed and non-HIV-exposed neonates. These results indicate that the presence of infections during pregnancy induces fetal immune activation with inflammation and increased activated MBC frequencies in neonates. The immunologic significance and long-term health consequences of these differences warrant further investigation.

Adipose-derived mesenchymal stem cells ameliorate the inflammatory reaction in CLP-induced septic acute lung injury rats via sTNFR1.

We hypothesized that the adipose-derived mesenchymal stem cells (ADMSCs), which secrete high amounts of soluble molecules, such as soluble tumor necrosis factor receptor 1 (sTNFR1), may ameliorate sepsis-induced acute lung injury (ALI). A total of 120 male adult Sprague-Dawley rats were separated into four groups: the sham control (SC), sepsis induced by cecal ligation and puncture (CLP), CLP-ADMSCs, and CLP-sTNFR1 small interfering RNA (siRNA) groups; CLP groups underwent CLP and then received 1 × 106 ADMSCs with or without knockdown of sTNFR1 intravenously at 1 hr after surgery. Rats were killed at 3, 6, 24, and 48 hr after the SC or CLP procedures. 5-Ethynyl-2'-deoxyuridine-labeled ADMSCs extensively colonized the lungs at 6, 24, and 72 hr after injection. The lung wet/dry (W/D) weight ratios in the CLP group were higher than those in SC group; however, ADMSCs ameliorated the W/D weight ratios following CLP, and this effect was abolished by sTNFR1 siRNA treatment. The levels of serum sTNFR1 and interleukin-10 (IL-10) were higher in the CLP-ADMSCs group and lower in the SC group than in other groups; interestingly, these levels were higher in CLP and CLP-sTNFR1 siRNA groups than in SC group. Tumor necrosis factor-α and IL-6 levels increased significantly after CLP, and ADMSCs could alleviate these changes, but the effect was weakened by sTNFR1 siRNA treatment. The lung cell apoptosis and edema levels were consistent with IL-6 levels among all groups. Therapeutically administered ADMSCs secrete sTNFR1, which most likely protects against ALI in septic rats by ameliorating inflammation and lung edema.

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

ObjectiveInflammation plays a crucial role in the pathogenesis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Our study aimed to analyse previous inconsistent results of inflammatory markers in AD...

Levels of TNF alpha, Soluble TNF Receptors (sTNF-R1, sTNF-R2) in Bipolar Disorder.

Current evidence suggests that pro-inflammatory cytokines, particularly tumor necrosis factor alpha (TNF-α) may play an important role in the pathophysiology of bipolar disorder (BD). Our study aims to compare BD patients and controls in terms of serum TNF-α, soluble tumor necrosis factor receptor 1 and soluble tumor necrosis factor receptor 2 (sTNF-R1, sTNF-R2) levels in different phases of BD. Eighty-three patients with BD type 1 (27 manic, 22 depressive and 34 euthymic) and twenty-nine healthy controls were included in the study. Serum levels of TNF-α, sTNF-R1, sTNF-R2 levels were evaluated with ELISA kit. Levels of sTNF-R1 were showed a statistically significant difference between groups. Levels of sTNF-R1 were higher in depression or mania patients than euthymia patients and control subjects. A statistically significant difference in the serum level of sTNF-R1 between patients in acute episode (mania and depression) group and stabile (patients in euthymic episode and controls) group was found in logistic regression analysis. The probability of having acute episode increased threefold for each unit increase in serum level of sTNF-R1. There was no statistically significant difference between the mean serum values of TNF-α and sTNF-R2 between the groups. sTNF-R1 production was different between acute episode patients and controls or stable BD patients. The result of this study confirms that TNF-R1 may be a state marker representing disease activity for BD.