CD133+ Stem Cell Therapy Effects on Myocardial Regeneration Through Increased Vascular Endothelial Growth Factor Correlate with Cardiac Magnetic Resonance Imaging Results in Coronary Artery Bypass Graft Surgery Patients with Low Ejection Fraction.

BACKGROUND: Stem cell implantation has become a promising therapy for heart failure due to coronary heart disease (CHD). CD133+ stem cell therapy, together with increases of vascular endothelial growth factor (VEGF) and other growth hormones, can induce myocardial repair. OBJECTIVE: To prove that VEGF plays a role in cardiac regeneration. METHODS: Twenty-six patients with CHD and ejection fractions <35% from Harapan Kita Heart and Vascular Center, Jakarta, Indonesia, from 2016 to 2018 were randomized into 2 groups. The treatment group underwent coronary artery bypass graft (CABG) + CD133+ implantation, and the control group underwent CABG only. Six months later, perfusion and myocardial function were assessed by ejection fraction, wall motion score index (WMSI), ventricular dimensions, and scar size using cardiovascular magnetic resonance imaging. VEGF was assessed with enzyme-linked immunosorbent assay. RESULTS: There was significant improvement in ejection fraction (8.69% ± 9.49% versus 1.43% ± 7.87%, P = .04), WMSI (0.51 ± 0.48 versus -0.01 ± 0.21, P = .003), and scar size (25.46 ± 12.91 versus 27.32  ± 12.92 mm, P = .047) and a significant increase in blood VEGF levels  (61.05 ± 63.01 versus 19.88 ± 33.78 pg/mL, P = .01). Improvements in perfusion defects (13.69 ± 5.03 versus 11.53 ± 5.81 P = .32) and ventricular dimensions (-27.59 ± 84.48 versus -19.08 ± 36.79 mm, P = .06) were not statistically significant. CONCLUSION: CD133+ stem cell implantation improves myocardial function. The increase in VEGF levels is expected to continue improving restoration of myocardial function when myocardial perfusion improvement is still not optimal.

TL1A-DR3 Plasma Levels Are Predictive of HIV-1 Disease Control, and DR3 Costimulation Boosts HIV-1-Specific T Cell Responses.

Relative control of HIV-1 infection has been linked to genetic and immune host factors. In this study, we analyzed 96 plasma proteome arrays from chronic untreated HIV-1-infected individuals using the classificatory random forest approach to discriminate between uncontrolled disease (plasma viral load [pVL] >50,000 RNA copies/ml; CD4 counts 283 cells/mm3, n = 47) and relatively controlled disease (pVL <10,000 RNA copies/ml; CD4 counts 657 cells/mm3, n = 49). Our analysis highlighted the TNF molecule's relevance, in particular, TL1A (TNFSF15) and its cognate DR3 (TNFSRF25), both of which increased in the relative virus control phenotype. DR3 levels (in plasma and PBMCs) were validated in unrelated cohorts (including long-term nonprogressors), thus confirming their independence from CD4 counts and pVL. Further analysis in combined antiretroviral treatment (cART)-treated individuals with a wide range of CD4 counts (137-1835 cells/mm3) indicated that neither TL1A nor DR3 levels reflected recovery of CD4 counts with cART. Interestingly, in cART-treated individuals, plasma TL1A levels correlated with regulatory T cell frequencies, whereas soluble DR3 was strongly associated with the abundance of effector HLA-DR+CD8+ T cells. A positive correlation was also observed between plasma DR3 levels and the HIV-1-specific T cell responses. In vitro, costimulation of PBMC with DR3-specific mAb increased the magnitude of HIV-1-specific responses. Finally, in splenocytes of DNA.HTI-vaccinated mice, costimulation of HTI peptides and a DR3 agonist (4C12) intensified the magnitude of T cell responses by 27%. These data describe the role of the TL1A-DR3 axis in the natural control of HIV-1 infection and point to the use of DR3 agonists in HIV-1 vaccine regimens.

Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF.

BACKGROUND: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. METHODS: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. RESULTS: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. CONCLUSIONS: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.

Intraocular tumour necrosis factor ligand related molecule 1 A links disease progression of proliferative diabetic retinopathy after primary vitrectomy.

Tumour necrosis factor ligand related molecule 1 A (TL1A), a member of tumour necrosis factor superfamily, has been identified as a crucial regulator for vascular homeostasis and inflammation. However, the function of TL1A in diabetic retinopathy (DR) is largely unknown. This study aims to examine levels of TL1A in serum and intraocular fluid in patients with proliferative diabetic retinopathy (PDR), and to explore the correlation of intraocular TL1A with the prognosis of PDR progression after primary vitrectomy. Seventy-five patients (75 eyes) with PDR who underwent pars plana vitrectomy (PPV) and 19 patients (19 eyes) who received vitrectomy for idiopathic macular holes (IMH) as non-diabetic control group were enrolled in this prospective study. Serum, aqueous and vitreous fluid samples were collected during cataract and PPV surgery. Protein expressions of TL1A as well as other angiogenic and inflammatory cytokines in serum and intraocular fluid were measured. Correlations of intraocular TL1A concentrations with inflammatory cytokines were analyzed. We found both aqueous and vitreous TL1A levels were significantly higher in the PDR group than in control group (Paqueous  = 0.026; Pvitreous <0.001). Angiogenic and inflammatory cytokines such as VEGF, IL-6, IL-8, MCP-1, MIP-1α, and MIP-1ß were significantly higher in intraocular fluid in PDR group than in controls, which MCP-1 and MIP-1α showed positive correlation with intraocular TL1A levels. There is no significant difference in the levels of serum TL1A as well as other inflammatory cytokines between PDR patients and controls. Intraocular levels of TL1A were significantly lower in PDR progression group than in the stable group (Paqueous <0.001; Pvitreous <0.001). Multivariate logistic regression analyses revealed that lower levels of intraocular TL1A was an important risk factor for predicting PDR progression after primary PPV (ORaqueous  = 0.717, Paqueous  = 0.001; ORvitreous  = 0.684; Pvitreous  = 0.002). In conclusion, TL1A and multiple inflammatory cytokines were highly enriched in the intraocular fluid of PDR patients compared with the controls. Lower levels of intraocular TL1A were associated with development of PDR complications after primary PPV and might be used as prognostic factor in predicting the vitrectomy outcome in PDR patients.

Tumour necrosis factor like cytokine 1A levels and lesion complexity in non-smoking patients with coronary artery disease.

Background: Tumour necrosis factor like cytokine 1A (TL1A), which is a member of tumour necrosis factor alpha superfamily (TNF-α), is a novel indicator of atherosclerosis.Objective: Smoking is an established stimulant of TNF-α. We aimed to investigate whether TLA1 plays a role in the presence and complexity of coronary artery atherosclerosis, exclusively in non-smoking patients with CAD.Methods: We enrolled 103 participants in the study, who underwent coronary angiography for stable angina pectoris. We divided the study population into 2 groups: The CAD group consisted of 62 patients with CAD and the control group consisted of 41 subjects with non-CAD. SYNTAX and Gensini scores, indicating CAD severity and complexity, were analysed as well as TLA1 levels.Results: TLA1 levels was higher in patients with CAD than those in controls (228[119-824] vs 178[15-418]pg/ml, p < 0.001). Presence of CAD (ß ± SE = 106.29 ± 33.11, p = 0.002), Syntax score (ß ± SE= 6.57 ± 1.75, p = 0.012), and Gensini score (ß ± SE = 2.30 ± 0.65, p = 0.001) were found to be predictors of TL1A levels. Gensini score and Syntax score were positively correlated with TL1A levels (r = 0.420, p < 0.001, and r = 0.402, p < 0.001, respectively).Conclusions: Non-smoker CAD patients have higher TLA1 levels that are promising biomarker for diagnosing CAD and indicating CAD lesion complexity.

Oestrogen-deficiency induces bone loss by modulating CD14+ monocyte and CD4+ T cell DR3 expression and serum TL1A levels.

BACKGROUND: Oestrogen-deficiency induced by menopause is associated with reduced bone density and primary osteoporosis, resulting in an increased risk of fracture. While the exact etiology of menopause-induced primary osteoporotic bone loss is not fully known, members of the tumour necrosis factor super family (TNFSF) are known to play a role. Recent studies have revealed that the TNFSF members death receptor 3 (DR3) and one of its ligands, TNF-like protein 1A (TL1A) have a key role in secondary osteoporosis; enhancing CD14+ peripheral blood mononuclear cell (PBMC) osteoclast formation and bone resorption. Whether DR3 and TL1A contribute towards bone loss in menopause-induced primary osteoporosis however, remains unknown. METHODS: To investigate this we performed flow cytometry analysis of DR3 expression on CD14+ PBMCs isolated from pre- and early post-menopausal females and late post-menopausal osteoporotic patients. Serum levels of TL1A, CCL3 and total MMP-9 were measured by ELISA. In vitro osteoclast differentiation assays were performed to determine CD14+ monocyte osteoclastogenic potential. In addition, splenic CD4+ T cell DR3 expression was investigated 1 week and 8 weeks post-surgery, using the murine ovariectomy model. RESULTS: In contrast to pre-menopausal females, CD14+ monocytes isolated from post-menopausal females were unable to induce DR3 expression. Serum TL1A levels were decreased approx. 2-fold in early post-menopausal females compared to pre-menopausal controls and post-menopausal osteoporotic females; no difference was observed between pre-menopausal and late post-menopausal osteoporotic females. Analysis of in vitro CD14+ monocyte osteoclastogenic potential revealed no significant difference between the post-menopausal and post-menopausal osteoporotic cohorts. Interestingly, in the murine ovariectomy model splenic CD4+ T cell DR3 expression was significantly increased at 1 week but not 8 weeks post-surgery when compared to the sham control. CONCLUSION: Our results reveals for the first time that loss of oestrogen has a significant effect on DR3; decreasing expression on CD14+ monocytes and increasing expression on CD4+ T cells. These data suggest that while oestrogen-deficiency induced changes in DR3 expression do not affect late post-menopausal bone loss they could potentially have an indirect role in early menopausal bone loss through the modulation of T cell activity.

TNFSF/TNFRSF cytokine gene expression in sickle cell anemia: Up-regulated TNF-like cytokine 1A (TL1A) and its decoy receptor (DcR3) in peripheral blood mononuclear cells and plasma.

BACKGROUND: Sickle cell anemia (SCA), a disorder with an important inflammatory component, where vasoocclusion is major contributor to the disease pathophysiology. Pro-inflammatory cytokines play an important regulatory role in the process of inflammation. We investigated the expression TL1A/DR3/DcR3 cytokine signaling pathway in peripheral blood mononuclear cells (PBMC) and their corresponding plasma levels in SCA subjects who presented with acute painful episodes. MATERIALS AND METHODS: PBMC were isolated from the blood of SCA subjects and normal healthy controls. RNA isolated from PBMC was used for real time gene expression of TL1A/DR3/DcR3. Gene expression was compared in subgroups within SCA subjects with co-inherited fetal hemoglobin (HbF) or alpha-globin gene deletions. Plasma prepared from blood was used for determination of TL1A/DR3/DcR3 proteins by ELISA assays. RESULTS: In the PBMC of SCA subjects, expression of TL1A and DcR3 is elevated, while DR3 expression is lowered in comparison to normal control PBMC. In SCA subjects with HbF > 10%, TL1A/DcR3 expression is lower, while HbF < 10% is associated with increased TL1A/DcR3 expression. Moreover, subjects with HbF > 10% appear to have significantly fewer pain episodes in comparison to those with HbF < 10%. Deletion of alpha-globin genes appears to have no significant effect on TL1A/DR3/DcR3 expression. Circulating levels of TL1A, DR3 and DcR3 in plasma were significantly elevated in SCA subjects. CONCLUSIONS: Elevated TL1A and DcR3 expression in PBMC of SCA subjects during painful vasoocclusive crisis, suggest an altered TL1A expression may contribute to the pathophysiology of vasoocclusive crisis in SCA. HbF > 10% appears to moderate TL1A elevation, while HbF < 10% exacerbates TL1A/DcR3 responses. Furthermore, subjects with HbF > 10% have significantly lower pain episodes reported as compared to subjects with HbF < 10%.

Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis.

Recent findings showed elevated expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) in rheumatoid arthritis (RA) patients and arthritis mice. However, whether TL1A gene polymorphisms may correlate with RA susceptibility needs to be discussed. This case-control study was performed on 350 RA patients and 556 healthy subjects to identify TL1A genetic variants (rs3810936, rs6478109, and rs7848647) and their possible association with TL1A levels, susceptibility to and severity of RA. Odds ratio and 95% confidence interval were calculated to represent the correlation between TL1A polymorphisms and RA. The TL1A serum levels were evaluated. Results showed that frequencies of TC, TT + TC genotypes of rs3810936, rs7848647 in RA patients were significantly lower in RA patients compared with controls. Patients with C allele showed more severe disease course (disease activity index: erythrocyte sedimentation rate, rheumatoid factor) than in carriers of T allele. However, the allele or genotype frequencies of rs6478109 were not associated with RA. In addition, TL1A genetic variants conferred higher TL1A levels in RA patients compared with controls. In conclusion, these findings indicated an association between TL1A rs3810936, rs7848647 variation and the susceptibility of RA in a sample of Chinese individuals, and TL1A may correlate with severity of RA.

Increased circulating levels of tumor necrosis factor-like cytokine 1A and decoy receptor 3 correlate with SYNTAX score in patients undergoing coronary surgery.

OBJECTIVE: Chronic inflammation of the arteries is a critical mechanism responsible for coronary atherosclerosis. We aimed to determine if tumor necrosis factor (TNF)-like cytokine 1A (TL1A) and decoy receptor 3 (DcR3) were involved in promoting atherosclerosis. METHODS: We compared plasma levels of TL1A and DcR3 in patients with coronary artery disease (CAD) undergoing coronary artery bypass grafting (n=40) and patients without CAD group (n=37, normal coronary artery angiogram) by enzyme-linked immunosorbent assay. We also analyzed the correlation between CAD and SYNTAX scores. RESULTS: Plasma levels of TL1A and DcR3 were significantly higher in the CAD compared with the no-CAD group. Multivariate analysis showed that TL1A and DcR3 were significantly correlated with the presence of CAD, and receiver operating characteristic curve analysis indicated that both TL1A and DcR3 showed high sensitivity and specificity for diagnosing CAD. Furthermore, TL1A was positively and significantly correlated with SYNTAX score in CAD patients. CONCLUSIONS: CAD patients requiring coronary artery bypass grafting have high circulating levels of both TL1A and DcR3, which may thus be useful biomarkers for diagnosing severe CAD. Furthermore, plasma levels of TL1A correlate with SYNTAX score, supporting its potential use as an indicator of the severity of CAD.

Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease.

Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a "recall-by-genotype" bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD.

The role of novel cytokines in inflammation: Defining peripheral artery disease among patients with coronary artery disease.

Coronary artery disease (CAD) patients with concomitant peripheral artery disease (PAD) experience more extensive and calcified atherosclerosis, greater lesion progression and more common coronary events compared to patients with CAD only. To characterize the distinct features of this aggressive atherosclerotic disease, we studied novel cytokines that code different stages of atherogenesis. One hundred and eighty consecutive subjects (60 patients into each group of CAD+PAD, CAD and controls) were recruited among patients with stable angina pectoris scheduled for coronary angiography. An ankle-brachial index (ABI) ≤0.9 was determined as occlusive PAD. Fasting serum tumor necrosis factor (TNF)-like antigen 1A (TL1A) and its receptor death receptor 3 (DR3), NOGO-B (reticulon 4B) and its receptor NUS1, high-sensitivity C-reactive protein (hsCRP), A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1, 4, 5 and interleukin (IL) 6 levels were determined. Serum hsCRP and DR3/TL1A concentrations were similar and higher than controls in the CAD and CAD+PAD groups. Levels of NOGO-B and its receptor NUS1 were increased and ADAMTS-5 was decreased in patients with CAD+PAD. Independent predictors of ABI in multivariate analysis were smoking (B = -0.13, p = 0.04), NUS1 (B = -0.88, p < 0.001), ADAMTS-5 (B = 0.63, p < 0.001) and SYNTAX score (B = -0.26, p < 0.001). Similarly, smoking (OR = 5.5, p = 0.019), SYNTAX score (OR = 1.2, p < 0.001), NUS1 (OR = 14.4, p < 0.001), ADAMTS-5 (OR = 1.1, p < 0.001) and age (OR = 1.1, p = 0.042) independently predicted the involvement of peripheral vasculature in logistic regression. The diagnostic performance of these cytokines to discriminate CAD+PAD were AUC 0.79 ( p < 0.001) for NUS1 and 0.37 ( p = 0.013) for ADAMTS-5. We report herein that circulating cytokines can give clues to the ongoing atherosclerotic process and the extent of vascular involvement in which distinct features of ADAMTS-5 and NUS1 make them promising cytokines for future research.

Elevated levels of TL1A are associated with disease activity in patients with systemic sclerosis.

TL1A is a member of the TNF superfamily. It performs significantly in the pathogenesis of rheumatic and autoimmune diseases partly through regulating the Th17 pathway. The clinical implication of circulating TL1A in patients with systemic sclerosis (SSc) remains unclear, and correlation between TL1A and Th17-related cytokines in the pathogenesis of SSc needs to be discussed. We measured serum levels of TL1A and Th17-related cytokines by ELISA in 47 patients with SSc, 56 patients with SLE, and 53 healthy subjects, and investigated association of these cytokines with clinical manifestations and laboratory variables. TL1A in relation to Th17-related cytokines were examined. In addition, the transcript level of TL1A in peripheral blood mononuclear cells (PBMCs) was determined by real-time reverse transcription polymerase chain reaction (real-time PCR). Serum TL1A levels were higher in patients with SSc than in healthy controls (P = 0.001), but were lower compared with SLE patients (P = 0.004). Diffuse cutaneous SSc or limited cutaneous SSc patients reported elevated expression of TL1A than those in healthy controls (P = 0.002, P = 0.007). Patients with active disease showed significantly higher expression of TL1A when compared with less active disease (P = 0.014). SSc patients with arthritis, elevated IgG titer, ESR >30 mm/h, and CRP >5 mg/l displayed elevated expression of TL1A, respectively. Serum levels of IL-17 and IL-21 were increased in SSc patients compared with healthy controls and positively related to TL1A levels (r s = 0.373, P = 0.010; r s = 0.370, P = 0.011, respectively). Moreover, TL1A mRNA expression in PBMCs was significantly higher in patients with SSc compared with healthy controls (P < 0.001). TL1A may play a role in the development of SSc.

Changes in TL1A levels and associated cytokines during pathogenesis of diabetic retinopathy.

Tumor necrosis factor (TNF) ligand related molecule 1A (TL1A), also termed TNF superfamily member 15 and vascular endothelial growth inhibitor is important for tumorigenicity and autoimmunity. However, the function of TL1A in diabetic retinopathy (DR) remains to be elucidated. The present study established a diabetes mellitus (DM) rat model to investigate TL1A, vascular endothelial growth factor (VEGF), tumor necrosis factor­α (TNF­α) and interleukin­1ß (IL­1ß) expression levels in the retina, vitreous and serum of rats with DM at different stages (1 month group, 3 month group and 6 month group). The present study determined that TL1A expression levels in the retina and vitreous from the DM 1 month group were significantly lower compared with the control group. However, TL1A levels in the retina and vitreous were significantly increased in advanced stages of DM compared with the control group. Furthermore, the levels of VEGF in the retina and vitreous were significantly higher in the DM groups compared with the control group. The expression levels of TNF­α and IL­1ß in the retina and vitreous were significantly higher in DM 3 month and 6 month groups compared with the control group. It is of note that the expression levels of TL1A were significantly lower in the DM 1 and 3 month groups compared with the control group; however, they were significantly increased in the DM 6 month group compared with the DM 3 month group. The expression levels of VEGF, TNF­α and IL­1ß in blood serum have been observed to exhibit similar expression change dynamics as those of the retina and vitreous. Therefore, these findings suggest that TL1A may be a protective factor of DR, and may provide a rationale for the development of novel therapeutic strategies to treat DR.

Serum decoy receptor 3 levels are associated with the disease activity of MPO-ANCA-associated renal vasculitis.

Type 17 T-helper (Th17) cells have been suggested to be involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Th17 cell proliferation is promoted by tumor necrosis factor (TNF)-like ligand 1A (TL1A), which binds to death receptor 3 (DR3) expressed on Th17 cells. Decoy receptor 3 (DcR3) is known to block the TL1A-DR3 pathway by binding TL1A. To evaluate the Th17-TL1A systems as disease activity markers in AAV, we investigated the serum levels of TL1A and DcR3 in AAV patients. Serum IL-17, IL-23, TL1A, and DcR3 were measured by ELISA in 24 AAV patients with microscopic polyangiitis before the initial treatment, 24 AAV patients during remission, and 20 control subjects. There were no significant differences in serum IL-17, IL-23, and TL1A levels among the active-vasculitis patients, inactive-vasculitis patients, and controls. The mean serum DcR3 level was significantly higher in the active-vasculitis patients than in the inactive-vasculitis patients and controls (P < 0.0001, respectively). There were significant positive correlations between the serum DcR3 levels and Birmingham Vasculitis Activity Score (BVAS), myeloperoxidase (MPO)-ANCA titers, white blood cell counts, serum creatinine levels, and serum C-reactive protein levels. In a multiple regression analysis, there was a significant positive correlation between the serum DcR3 level and BVAS (ß = 0.650, P = 0.0462). The mean BVAS level was significantly higher in the active-vasculitis patients with high serum DcR3 levels than in those with the low serum DcR3 levels (P = 0.0202). The serum level of DcR3 may be a useful marker for disease activity in AAV.

The role of vascular endothelial growth factor and vascular endothelial growth inhibitor in clinical outcome of traumatic brain injury.

OBJECTIVES: Tumor necrosis factor superfamily-15 (TNFSF15) also known as vascular endothelial growth inhibitor (VEGI) is a cytokine that modulates anti-angiogenesis and inflammation. Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability following traumatic brain injury (TBI). The balance of VEGF and VEGI may play a key role in the maintenance of vascular and immune system homeostasis in the brain. However, the dynamic changes of circulating VEGF and VEGI after traumatic brain injury (TBI) and the correlation between plasma VEGF and plasma VEGI remains obscure. In this study, we were to investigate whether circulating VEGF and VEGI can be used as prognostic markers for patients with TBI. PATIENTS AND METHODS: A prospective clinical study was conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Tianjin Huanhu Hospital (Tianjin, China). 40 patients and 30 healthy controls were recruited. The recruited subjects were aged over 18 with randomized gender and GCS. 1mL of blood was withdrawn on 1, 4, 7, 14, and 21days after TBI. Blood samples were centrifuged at 3000rpm and the supernatants were used to measure VEGF and VEGI by ELISA kit. RESULTS: 1) Circulating VEGF in TBI patients was decreased on the 1st day after TBI, then climbed up on the 4th day, reaching a maximum level on the14th day after TBI, as compared to normal controls. VEGF level returned to normal level on 21th day after TBI. 2) Circulating VEGI in TBI patients was decreased on the 1st and 4th day after TBI, then climbed up on the 7th day after TBI, reaching a maximum level on 14th day after TBI, as compared to normal controls. VEGI levels declined to normal level on 21th day after TBI. 3) There was a significant positive correlation between circulating VEGF and VEGI. 4) However, TBI patients whose conditions had improved exhibited lower VEGF levels 7days after TBI when compared to TBI patients whose condition had deteriorated. Survivors exhibited higher VEGI levels 7days after TBI when compared to non-survivors. 5)TBI patients whose condition had improved exhibited higher VEGI levels when compared to TBI patients whose condition had deteriorated 21days after TBI. Patients with mild TBI exhibited higher VEGI levels than those with moderate and severe TBI 21days after TBI. 6) A lower rate of recovery and higher hospital mortality were found in patients with VEGF/VEGI ratio≥2.366 as compared to those with VEGF/VEGI ratio<2.366 7days after TBI. CONCLUSIONS: 1) VEGF level positively correlates with VEGI after TBI. 2) The elevation of VEGF exhibits an adverse effect from 4 to 14days after TBI while it has an advantageous effect from 14 to 21days after TBI. Increasing VEGI levels are beneficial in recovery after TBI. Controlling the ratio of VEGF/VEGI may benefit the clinical outcome following TBI.

TL1A as a Potential Local Inducer of IL17A Expression in Colon Mucosa of Inflammatory Bowel Disease Patients.

Interaction between TL1A and death receptor 3 (DR3) co-stimulates T cells, induces production of several pro-inflammatory cytokines and has been linked to pathogenesis of inflammatory bowel disease (IBD). This study aimed to establish a link between expression of TL1A and selected TL1A-induced pro-inflammatory cytokines involved in IBD pathogenesis (IL-4, IL-13, IL-17A and IFN-γ) and to investigate a connection between serum concentration of TL1A in patients with IBD and activation of peripheral blood T cells. Elevated levels of IL-4 (2.91-fold) and IL-13 (4.05-fold) mRNA were detected in the inflamed colon mucosa of patients with ulcerative colitis (UC), IFN-γ mRNA was upregulated (3.23-fold) in the inflamed colon mucosa of patients with Crohn's disease (CD), whereas upregulation of IL-17A and TL1A mRNA was present in the inflamed colon mucosa of patients with both CD and UC (IL-17A: 4.48-fold and 2.74-fold, TL1A: 3.19-fold and 3.22-fold, respectively) vs. control subjects. We did not detect any changes in DR3 mRNA expression in the investigated groups of patients. TL1A mRNA level in colon mucosa of patients with IBD correlated only with the level of IL-17A mRNA but no other investigated cytokines. In colon mucosa, expression of TL1A and DR3 was localized to enterocytes and lamina propria mononuclear cells. We did not find any correlation between serum concentrations of TL1A and IL-17A or changes of CD4(+) or CD8(+) lymphocytes phenotype in patients with IBD. Therefore, our data indicate that TL1A may contribute to pathogenesis of IBD via local but not systemic induction of IL-17A but not IL-4, IL-13 or IFN-γ.

Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients.

TL1A is a TNF-like cytokine which has been shown to co-stimulate TH1 and TH17 responses during chronic inflammation. The expression of this novel cytokine has been investigated in inflammatory disorders like rheumatoid arthritis and inflammatory bowel disease, but little is known about expression and induction in psoriasis. Indeed, the pathogenesis in psoriasis is still not fully understood and it is speculated that cytokines other than TNF-α are important in subsets of patients. Also, for patients with severe disease that are treated with systemic anti-TNF-α blockade, novel candidates to be used as disease and response biomarkers are of high interest. Here, we demonstrate TL1A expression in biopsies from psoriatic lesions. Also, we investigated spontaneous and induced TL1A secretion from PBMCs and blood levels from a cohort of psoriasis patients. Here, increased spontaneous secretion from PBMCs was observed as compared to healthy controls and a small subset of patients had highly elevated TL1A in the blood. Interestingly, activation of PBMCs with various cytokines showed a decreased sensitivity for TL1A activation in psoriasis patients compared to healthy controls.TL1A levels in blood and biopsies could not be correlated with disease activity with this patient cohort. Thus, additional large-scale studies are warranted to investigate TL1A as a biomarker.

Serum and synovial fluid levels of tumor necrosis factor-like ligand 1A and decoy receptor 3 in rheumatoid arthritis.

OBJECTIVE: To measure the levels of Tumor necrosis factor (TNF)-like ligand 1A (TL1A) and decoy receptor 3 (DcR3) in serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA). To evaluate the effect of recombinant human (rh) TL1A on interleukin (IL)-17 production and IL-17mRNA expression. METHODS: The serum and SF levels of TL1A and DcR3, and the production of IL-17 by rhTL1A-treated PBMC were measured by enzyme-linked immunosorbent assay (ELISA). The expression of IL-17 mRNA by rhTL1A-treated PBMC was measured by real-time reverse transcriptase polymerase chain reaction (RT-PCR). We also tested the change of TL1A and DcR3 level following TNF-α blockade therapy. RESULTS: Serum TL1A and DcR3 levels were higher in RA patients. This increase was more significant in RF and anti-CCP positive patients. TL1A and DcR3 levels were higher in SF samples than in paired sera. TL1A and DcR3 decreased after anti-TNF treatment. rhTL1A increased the production of IL-17 protein and the expression of IL-17mRNA. CONCLUSION: TL1A and DcR3 may be of pathogenic and potentially of therapeutic importance in RA patients.

Circulating levels of TNF-like cytokine 1A correlate with reflected waves and atherosclerosis extent and may predict cardiac death in patients with stable coronary artery disease.

BACKGROUND: TNF-like cytokine 1A (TL1A)-mediated interactions are involved in atheromatic plaque formation. In stable coronary artery disease (CAD) we examined whether circulating TL1A levels correlate with coronary and/or peripheral atherosclerosis extent and predict future cardiovascular events. METHODS: In this cross-sectional study, peripheral vascular studies and TL1A serum measurements were performed in 122 consecutive patients with angiographically confirmed CAD who were followed for a median of 41.9 months. TL1A levels were compared against controls (n = 63) and 20 patients with acute coronary syndrome (ACS). RESULTS: TL1A was higher in ACS than the 2 other groups (p < 0.001). In stable CAD, after adjustment for traditional risk factors independent positive correlations between TL1A serum levels and reflected waves (p = 0.049), and carotid atheromatic plaque score (p = 0.049) were evident. In stable patients with a history of ACS, TL1A levels correlated with worse endothelial function (p = 0.006), extent of CAD assessed by Gensini score (p = 0.042), and cardiac mortality (p = 0.051). CONCLUSIONS: This pilot study suggests that serum TL1A measurements are of clinical value in CAD. Studies on the pathogenetic role of TL1A in atherosclerosis and its sequelae are warranted.

TNF-like ligand 1A is associated with the pathogenesis of psoriasis vulgaris and contributes to IL-17 production in PBMCs.

TNF-like ligand 1A (TL1A), a newly identified member of the TNF superfamily, has been proved as an important mediator of inflammation and critically involved in the pathogenesis of rheumatoid arthritis and several other autoimmune diseases. The aim of our study was to determine the possible role of TL1A in the pathogenesis of psoriasis. In this study, serum levels of TL1A in patients with psoriasis vulgaris (PV) and atopic dermatitis (AD) were detected by enzyme-linked immunosorbent assay (ELISA). Then, peripheral blood mononuclear cells (PBMCs) from patients with PV were isolated, the mRNA expression of TL1A was measured by real-time quantitative PCR. The effects of TL1A on the production of T cell cytokines, such as IL-17, IFN-γ, IL-4 and IL-10 in PBMCs were determined. We demonstrated that serum TL1A levels were significantly elevated in patients with PV but not in patients with AD. Besides, the high serum TL1A levels in patients with PV decreased after treatment. PBMCs derived from psoriatic patients showed significantly increased TL1A mRNA levels. Soluble TL1A synergized with IL-23 to stimulate PBMCs from patients with PV to produce IL-17. Taken together, these findings strongly suggest that TL1A may play a role in the pathogenesis of PV.