Serum sTRAIL Levels Research Articles

Serum-soluble TRAIL: a potential biomarker for disease activity in myositis patients.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF super-family, which is involved in the regulation of immune response and pathogenesis of autoimmune diseases, including polymyositis (PM) and dermatomyositis (DM). In this study, we examined the level and origin of serum-soluble TRAIL (sTRAIL) in patients with PM and DM and analyzed its association with disease activity and clinical features. 11 PM patients, 33 DM patients, and 20 healthy controls were enrolled in this study. Clinical features were recorded when admitted, and disease activity was evaluated by myositis disease activity assessment visual analogue scale (MYOACT). TRAIL expression in muscle tissues was detected by immunohistochemistry. Serum sTRAIL levels were measured by enzyme-linked immunosorbent assay. The expression of membrane TRAIL (mTRAIL) and its receptors, including DR4 and DR5, on circulating T cells was analyzed by flow cytometry. TRAIL was expressed in infiltrated inflammatory cells in muscle tissues from patients. The serum sTRAIL level was markedly increased in patients and was positively correlated with the disease activity. Serum sTRAIL was decreased after therapy in patients and was specifically higher in patients with dysphagia, but lower in patients with autoantibody Jo-1 positive. The frequency of mTRAIL and its receptors on circulating T cells from patients were significantly elevated than that from healthy controls. The serum sTRAIL could be a biomarker for evaluating the disease activity of PM and DM, and targeting the generation of TRAIL in T cells might be a potential approach in the treatment of PM and DM.

Autosomal Dominant Polycystic Disease is Associated with Depressed Levels of Soluble Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by multiple, large renal cysts and impaired kidney function. Although the reason for the development of kidney cysts is unknown, ADPKD is associated with cell cycle arrest and abundant apoptosis of renal tubular epithelial cells. We asked whether serum-soluble TNF-related apoptosis-inducing ligand (sTRAIL) might underlie ADPKD. Case-control study. Serum sTRAIL levels were measured in 44 patients with ADPKD and 18 healthy volunteers. The human soluble TRAIL/Apo2L ELISA kit was used for the in vitro quantitative determination of sTRAIL in serum samples. Mean serum sTRAIL levels were lower in patients with ADPKD as compared to the control group (446.9±103.1 and 875.9±349.6 pg/mL, p<0.001). Serum sTRAIL levels did not differ among stages of renal failure in patients with ADPKD. There was no correlation between serum sTRAIL levels and estimated glomerular filtration rate in patients with ADPKD (p>0.05). Our results show that ADPKD patients have depressed sTRAIL levels, indicating apoptosis unrelated to the stage of chronic renal failure.

The Role of Tumor Necrosis Factor Alpha and TNF Superfamily Members in Bone Damage in Patients with End-Stage Chronic Obstructive Lung Disease Prior to Lung Transplantation.

A disequilibrium of tumor necrosis superfamily (TNF) members, including the serum osteoprotegerin, soluble receptor activator of nuclear factor-κB ligand, soluble TNF-related apoptosis-inducing ligand and TNF-α, was associated with the occurrence of a reduced skeletal mass and osteoporosis in male patients with end-stage chronic obstructive pulmonary disease (COPD). The purpose of this study was to explore the associations between serum biomarkers of tumor necrosis factor (TNF) superfamily and body and bone compositions in end-stage COPD males. Pulmonary function, T-score at the lumbar spine and femoral neck, lean mass, serum osteoprotegerin (OPG), soluble receptor activator of nuclear factor-κB ligand (sRANKL), TNF-α and its receptors (sTNFR-I, sTNFR-II) and soluble TNF-related apoptosis-inducing ligand (sTRAIL) levels were evaluated in 48 male patients with end-stage COPD and 36 healthy male volunteers. OPG was lower in male COPD patients than in control subjects, whereas sRANKL, TNF-α and its receptors were higher. The serum sTRAIL level showed a tendency to increase compared with that of healthy subjects (P=0.062). Serum OPG showed a positive correlation with bone density. In contrast, serum TNF-α, sRANKL and sTRAIL were inversely associated with pretransplant bone density. We have noted the appearance of statistically significant inverse relationships between lean mass values and TNF-α, sTNFR-I and II and sRANKL levels in male COPD patients. Moreover, there was a negative correlation between sTRAIL levels with airway obstruction (P=0.005) and hypercapnia (P=0.042) in advanced COPD patients. Through a multiple linear regression analysis, our study revealed that a disequilibrium of TNF family members was strongly associated with the occurrence of a reduced skeletal mass and osteoporosis. These results provide further evidence that abnormal levels of TNF superfamily molecules may cause not only a decrease in BMD, but also lower muscle mass in end-stage COPD.

Increased Serum S-TRAIL Level in Newly Diagnosed Stage-IV Lung Adenocarcinoma but not Squamous Cell Carcinoma is Correlated with Age and Smoking

Lung cancer is the leading cause of cancer mortality in the world. Many factors can protect against or facilitate its development. A TNF family member TRAIL, has a complex physiological role beyond that of merely activating the apoptotic pathway in cancer cells. Vitamin D is converted to its active form locally in the lung, and is also thought to play an important role in lung health. Our goal was to investigate the possible clinical significance of serum sTRAIL and 1,25-dihydroxyvitamin D(3) levels in patients with non-small cell lung cancer (NSCLC). Totals of 18 consecutive adenocarcinoma and 22 squamous cell carcinoma patients with stage-IV non-small cell lung cancer referred to our institute were included in this study. There were 12 men and 6 women, with ages ranging from 38 to 97 (mean 60.5) years with adenocarcinoma, and 20 men and 2 women, with ages ranging from 46 to 80 (mean 65) years with squamous cell carcinoma. Serum levels of sTRAIL and 1,25-dihydroxyvitamin D(3) were measured in all samples at the time of diagnosis. sTRAIL levels in NSCLC patients were higher than in the control group. Although there was no correlation between patient survival and sTRAIL levels, the highest sTRAIL levels were correlated with age and cigarette smoking in the adenocarcinoma patients. sTRAIL level in healthy individuals were correlated with serum 1,25-dihydroxyvitamin D(3). Serum sTRAIL concentrations were increased in NSCLC patients, and correlated with age and smoking history, but not with overall survival.

Mechanisims of asthma and allergic disease - 1088. Increased serum strail level in newly diagnosed stave-iv lung adenocarcinoma but not sqamous cell carcinoma, is correlated with age and smoking

Methods Consecutive 18 adenocarcinoma and 22 squamous cell carcinoma patients of non-small cell lung cancer referred to our institute were included in this study. There were 12 men and 6 women, ages ranged from 38 to 97 years, with adenocarcinoma and average of 60.5 years. And there were 20 men and 2 women, ages ranged from 46 to 80 years, with squamous cell carcinoma and average of 64.95 years. Curative resection was performed for all patients. Serum levels of sTRAIL and 1,25-dihydroxyvitamin D(3) were measured in the samples of time of diagnosis.

Relationship between serum levels of tumour necrosis factor‐related apoptosis‐inducing ligand and the survival of Chinese peritoneal dialysis patients

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can counteract inflammation and atherosclerosis, both common causes of morbidity in peritoneal dialysis (PD) patients. We examined the relation between serum soluble TRAIL (sTRAIL) levels and the outcome of Chinese PD patients. We studied 116 new PD patients (67 males, age 56.7 ± 13.4 years). Baseline serum sTRAIL level was determined and grouped to tertiles 1 (lowest) to 3 (highest). All patients were followed for 20.9 ± 7.0 months. Patient survival was 83.4%, 74.2% and 100% for tertiles 1 to 3, respectively, at 24 months (P = 0.021). Multivariate Cox regression analysis showed that serum sTRAIL level was an independent predictor of patient survival after adjusting for confounding factors (adjusted hazard ratio 0.962, 95% confidence interval [CI] 0.935-0.991, P = 0.010). A higher baseline serum sTRAIL level was associated with a better survival of PD patients. The detailed mechanism deserves further investigation.

Increased serum sTRAIL levels were correlated with survival in bevacizumab-treated metastatic colon cancer

BackgroundColorectal cancer is the third most common cancer and the third leading cause of cancer-related death. Bevacizumab is a humanized monoclonal antibody developed against vascular endothelial growth factor (VEGF) for the treatment of metastatic cancer. The parameters of RECIST (Response Evaluation Criteria for Solid Tumors) are not adequate to detect important treatment effects and response. Our goal was to evaluate the possibility of using sTRAIL (serum-soluble TNF-related apoptosis-inducing ligand) and VEGF as markers of treatment efficacy and prognosis in patients with metastatic colon cancer.MethodssTRAIL and VEGF levels were measured by ELISA in the sera of 16 bevacizumab-treated metastatic colon cancer patients and 10 presumably healthy age-matched controls. The measurements were taken before and after treatment for comparison purposes.ResultsElevated levels of sTRAIL were found in seven out of 16 patients after bevacizumab treatment. Although these patients had a median survival time of 20.6 months, the remaining bevacizumab-treated patients who did not show an increase in sTRAIL had a median survival time of 9.4 months. As expected, serum VEGF levels were decreased in all patients who received bevacizumab therapy and showed no correlation between serum VEGF levels and patient survival (data not shown).ConclusionsSerum sTRAIL levels might be a useful predictor of prognosis in metastatic colon cancer, in the early evaluation stages following bevacizumab treatment.

277 Serum Soluble Trail Levels in Patients With Severe Persistent Allergic Asthma

BackgroundThe pathogenesis of allergic asthma and other allergic conditions are believed to be closely interrelated because of the similar dynamics of allergy-inducing cells and molecules, and the independent evidence for their clinical overlap. In this study we compare the diseases and the effect of Omalizumab treatment on the dynamics of cell apoptosis regulating molecules.MethodsIn the first group, 6 males and 8 females (a total of 14 patients) were selected with severe persistent asthma with a mean age of 42.4 years (Table I). All patients received omalizumab therapy for 4 months, with treatment administered every 2 weeks. Symptoms and severity of allergic reactions were recorded before and after treatment with omalizumab. Clinical changes and adverse effects were assessed and recorded at each patient visit. The second group consisted of 14 newly diagnosed allergic asthma patients with mean age was 43.8 years. All of these patients were followed up in the Immunology Allergy Clinic of the Antalya Education and Training Hospital, and were evaluated by clinical status. The third group consisted of 14 healthy volunteers, with no difference in age and sex (mean age was 43,3 years. Serum sTRAIL levels in all individuals (patients and healthy controls) were measured by a sandwich enzyme-linked immunosorbent assay (Diaclone, France).ResultsThere were no differences between the healthy controls, newly diagnosed allergic asthma patients and non-treated severe persistent allergic asthma patients during the active phase (P < 0.05). Interestingly, the variance levels in patients who received omalizumab treatment were significantly lower than the healthy controls.ConclusionsIn summary, we speculate that the physiological functions of sTRAIL in allergic conditions, and the elucidation of the molecular mechanisms by which sTRAIL: TRAIL receptor signals cells, will be of significant interest to the scientific allergy community in the coming years. Our study provides a novel perspective on severe persistent allergic asthma and the effect of omalizumab treatment on cell apoptosis, using serum sTRAIL measurements.

STRAIL Serum Levels and TRAIL 1595 Genotypes: Associations with Progress and Prognosis of Colorectal Carcinoma

Programmed cell death called apoptosis, plays an important role in the development and maintenance of tissue homeostasis and abnormalities in apoptotic function have been known as important events in the pathogenesis of many cancer types, such as colorectal cancer. It has been shown that both the membrane-bound TRAIL and sTRAIL can induce apoptosis in several tumor types by activating death receptors. Our study was to investigate the existence of TRAIL 1595 C/T SNP in colorectal cancer patients and possible effects of this substitution on serum levels of sTRAIL. In the present study, TRAIL 1595 C/T polymorphism was genotyped in 76 patients with colorectal cancer and 98 healthy subjects using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There were no significant differences in the distribution of TRAIL 1595 C/T genotypes and frequencies of the alleles between colorectal cancer patients and controls. The increased frequency of TRAIL 1595 homozygotes genotypes in patients who had advanced tumour stage was statistically significant (p = 0.0082). Serum sTRAIL levels in the colorectal patients with CT genotype were lower than those of patients with early tumor stage (p = 0.028). The decreased sTRAIL levels were observed in the patients with distant metastasis and CT genotype (p = 0.023). Our findings have suggested that TRAIL 1595 C/T genotypes and sTRAIL levels might be associated with the progression of colorectal cancer in Turkish population.

Serum-soluble TRAIL levels in patients with severe persistent allergic asthma: its relation to omalizumab treatment.

SummaryBackgroundIn this study we compare the Omalizumab treatment modality in the dynamics of cell apoptosis regulating molecules in both severe persistent asthma patients who had no other any allergic disease, newly diagnosed patients with allergic asthma, and healthy volunteers.Material/MethodsSevere persistent allergic asthma patients were subjected to measurement of serum soluble TRAIL (TNF-related apoptosis-inducing ligand) levels during the active disease phase and the stable phase which occurred 4 months after Omalizumab treatment. Serum sTRAIL concentrations were measured by a solid phase sandwich enzyme-linked immunosorbent assay. Concentration levels were compared with those of age- and sex-matched newly diagnosed patients with allergic asthma, and healthy controls. All assays were carried out in duplicate. Total serum IgE levels, antinuclear antibody (ANA), rheumatoid factor (RF), hepatitis markers, C3, C4 and eosinophil levels were evaluated in all patients.ResultsANA, RF, hepatitis markers were negative in all patients. Complement 3 and 4 levels were normal in all patients. Prick tests in all patients were detected in mite and grass allergy. These results correlated with specific IgE. There were no differences between the healthy controls, newly diagnosed allergic asthma patients, and non-treated severe persistent allergic asthma patients during the active phase. Interestingly, the levels in variances of the patients who had the effective omalizumab treatment were significantly lower than the healthy controls, while the mean values were not statistically significant.ConclusionsOur study gives a different perspective on severe persistent allergic asthma and omalizumab treatment efficacy at the cell apoptosis-linked step by the serum sTRAIL levels.

The circulating soluble TRAIL is a negative marker for inflammation inversely associated with the mortality risk in chronic kidney disease patients

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and an inadequate inflammatory response which may account for the high morbidity and mortality observed in this population. In vitro and preclinical evidence suggests that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) might be involved in both the atherosclerosis pathway and modulation of the inflammatory response. The aim of the present study was thus to (i) determine serum levels of soluble TRAIL (sTRAIL) in a cohort of CKD patients, (ii) assess the relationship between sTRAIL and other inflammatory biomarkers (C-reactive protein and albumin) and (iii) evaluate the association between serum sTRAIL levels and the mortality risk. One hundred and thirty patients (mean +/- SD age: 67 +/- 12; 62% males; 8% at CKD stage 2, 26% at stage 3, 27% at stage 4, 8% at stage 5 and 31% at stage 5D) were assayed for sTRAIL and the selected biochemical parameters and then prospectively monitored for mortality. CKD stage 5D patients had significantly lower serum sTRAIL levels (median: 46 pg/ml) than patients at CKD stages 2 and 3 (median: 62 pg/ml) or stages 4 and 5 (median: 71 pg/ml). There was no correlation between serum sTRAIL and the estimated glomerular filtration rate (GFR) (r(2) = 0.017, P = 0.22) in pre-dialysis patients. In a multivariate regression analysis, the body mass index (beta = 1.48, P = 0.001) and the serum C-reactive protein (CRP) level (beta = -8.841, P < 0.0001) were independently associated with serum sTRAIL. During follow-up (mean: 772 +/- 286 days), 36 patients died (19 from cardiovascular events, 8 from infectious events and 9 from other causes). The lowest sTRAIL levels (first tertile) were associated with the worst all-cause survival (P = 0.010). Cox regression analyses (with non-cumulative models including age, albumin and CRP as covariates) confirmed the low serum sTRAIL level (first tertile) as an independent predictor of all-cause mortality. Circulating sTRAIL is a negative marker for inflammation and is inversely associated with the mortality risk in CKD patients. Further studies are needed to better understand the role of sTRAIL as an inflammatory marker and to confirm its protective role in the CKD population.

IFNα Therapy Up-Regulates Serum Soluble TRAIL Levels and Induces Marked TRAIL mRNA Expressions in Polymorphonuclear Neutrophils in Chronic Myeloid Leukemia Patients.

[Purpose] Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is an interferon α (IFN)-induced, apoptosis-inducing molecule. TRAIL is one of the promising reagents for therapeutic use in combination with imatinib in chronic myeloid leukemia (CML). A previous report showed that IFN-induced TRAIL is only weakly expressed on cell surface but is mainly secreted as a soluble form (sTRAIL) by polymorphonuclear neutrophils (PMNs) (and also by monocytes) in healthy individuals. Up to now, however, whether sTRAIL is actually released into serum in CML patients and whether its serum level is up-regulated during in vivo IFN therapy are unsolved issues. To assess the significance of sTRAIL, we examined serum sTRAIL levels by ELISA in total 40 (36 in CP, 4 in BP) CML patients either prior to or undergoing IFN therapy.[Results] Serum sTRAIL were detectable in untreated CML patients (1258±560 pg/ml, n=25), which levels were substantially comparable to those in healthy donors (1159±343, n=10). Serum sTRAIL levels significantly increased in patients during IFN therapy (1801±712, n=18) compared to those in untreated patients (P=0.009). This IFN-induced up-regulation of serum sTRAIL was further confirmed in all seven patients whom we could analyze both before and during the therapies (before 1228±396 vs. during 1956±914, P=0.037). As for initial sTRAIL levels, among the restricted patients group who later showed any cytogenetic response (n=15), there was a tendency that initially higher serum sTRAIL levels accompanied better cytogenetic responses (CCyR: 1873±719, PCyR: 1130±204, minor CyR: 830±267, P=0.03), indicating that the initial sTRAIL level may have some relation with the later response to IFN therapy. Next, to investigate the source of the sTRAIL secretion into serum, we assessed TRAIL mRNA expressions in PMNs in the peripheral blood by RQ-PCR. Again, TRAIL mRNA expressions in patients during IFN therapy (n=22) significantly increased compared to those in untreated patients (n=16) (TRAIL/GAPDH: before 1.4 vs. during 8.0, P=0.005). This IFN-induced up-regulation of TRAIL mRNA expression in PMNs was confirmed in all 16 patients whom we could analyze both before and during IFN therapies (before 3.7 vs. during 21.3, P=0.018). In vitro IFN stimulation of PMNs in five untreated patients showed marked induction (10 to 30 fold) of TRAIL mRNA at 12h, while induction of FAS mRNA stayed rather low (1 to 2 fold). Furthermore, IFN concentration-dependent accumulations of sTRAIL into the culture supernatants were observed for up to 48 h. Next, we assessed TRAIL mRNA expressions in purified CD34-positive cells in the bone marrow. TRAIL mRNA expressions were also detectable, and the mRNA levels significantly increased in patients during IFN therapy (n=37), compared to those in untreated patients (n=17) (P=0.02). This IFN-induced up-regulation of TRAIL mRNA was confirmed in nine patients whom we could analyze both before and during the therapies (P=0.01), indicating that even immature CML elements are responsive to IFN and may contribute to sTRAIL release in the microenvironment.[Conclusion] This is the first evidence showing that IFN, in vivo, provokes the release of sTRAIL when administered systematically in CML patients. The main source of the serum sTRAIL is probably PMNs in CML patients. We suspect that one of the mechanisms of anti-proliferative action of IFN on CML is sTRAIL secreted into serum. Our findings also give rationale for the use of IFN (or recombinant sTRAIL) in combination with imatinib in CML patients.

Expression of TRAIL, DR4, and DR5 in kidney and serum from patients receiving renal transplantation

Renal transplantation is the best treatment of some end-stage renal diseases. Unfortunately, not every transplant is successful due to the rejection or dysfunction of the transplanted kidney. Many cytokines participate in rejection by inducing inflammation or apoptosis. In this study, the expressions of TRAIL, DR4, and DR5 in rejected renal tissue and of serum soluble TRAIL (sTRAIL) in patients with kidney rejection were investigated by immunohistochemical staining and sandwich enzyme-linked immunosorbent assay, respectively. The results showed that the expression of TRAIL, DR4 and DR5, and serum sTRAIL levels were markedly upregulated among renal transplant patients. Since both membrane and soluble forms of TRAIL can induce apoptosis of DR4/DR5-expressing cells via recruiting FADD and caspase 8, elevated TRAIL and its receptors may participate in renal graft rejection.