ß2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function.

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of ß2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.

EIF2S2 transcriptionally upregulates HIF1α to promote gastric cancer progression via activating PI3K/AKT/mTOR pathway.

Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) is a protein that controls protein synthesis under various stress conditions and is abnormally expressed in several cancers. However, there is limited insight regarding the expression and molecular role of EIF2S2 in gastric cancer. In this study, we identified the overexpression of EIF2S2 in gastric cancer by immunohistochemical (IHC) staining and found a positive correlation between EIF2S2 expression and shorter overall survival and disease-free survival. Functionally, we revealed that EIF2S2 knockdown suppressed gastric cancer cell proliferation and migration, induced cell apoptosis, and caused G2 phase cell arrest. Additionally, EIF2S2 is essential for in vivo tumor formation. Mechanistically, we demonstrated that EIF2S2 transcriptionally regulated hypoxia induicible factor-1 alpha (HIF1α) expression by NRF1. The promoting role of EIF2S2 in malignant behaviors of gastric cancer cells depended on HIF1α expression. Furthermore, the PI3K/AKT/mTOR signaling was activated upon EIF2S2 overexpression in gastric cancer. Collectively, EIF2S2 exacerbates gastric cancer progression via targeting HIF1α, providing a fundamental basis for considering EIF2S2 as a potential therapeutic target for gastric cancer patients.

The Role of Protein Quantity Control in Polyglutamine Spinocerebellar Ataxias.

Polyglutamine spinocerebellar ataxias (polyQ SCAs) represent the most prevalent subtype of SCAs. The primary pathogenic mechanism is believed to be the gain-of-function neurotoxicity of polyQ proteins. Strategies such as enhancing the degradation or inhibiting the accumulation of these mutant proteins are pivotal for reducing their toxicity and slowing disease progression. The protein quality control (PQC) system, comprising primarily molecular chaperones and the ubiquitin‒proteasome system (UPS), is essential for maintaining protein homeostasis by regulating protein folding, trafficking, and degradation. Notably, polyQ proteins can disrupt the PQC system by sequestering its critical components and impairing its proteasomal functions. Therefore, restoring the PQC system through genetic or pharmacological interventions could potentially offer beneficial effects and alleviate the symptoms of the disease. Here, we will provide a review on the distribution, expression, and genetic or pharmacological intervention of protein quality control system in cellular or animal models of PolyQ SCAs.

Exploring the characteristics of Burkholderia gladioli pathovar cocovenenans: Growth, bongkrekic acid production, and potential risks of food contamination in wet rice noodles and vermicelli.

This research investigated the presence of Burkholderia gladioli pathovar cocovenenans (BGC) in wet rice and starch products, Tremella, and Auricularia auricula in Guangzhou, China. It examined BGC growth and bongkrekic acid (BA) production in wet rice noodles and vermicelli with varying rice flour, edible starch ratios, and oil concentrations. A qualitative analysis of 482 samples revealed a detection rate of 0.62%, with three positive for BGC. Rice flour-based wet rice noodles had BA concentrations of 13.67 ± 0.64 mg/kg, 2.92 times higher than 100% corn starch samples (4.68 ± 0.54 mg/kg). Wet rice noodles with 4% soybean oil had a BA concentration of 31.72 ± 9.41 mg/kg, 5.74 times higher than those without soybean oil (5.53 ± 1.23 mg/kg). The BA concentration correlated positively (r = 0.707, P < 0.05) with BGC contamination levels. Low temperatures (4 °C and -18 °C) inhibited BGC growth and BA production, while higher storage temperatures (26 °C and 32 °C) promoted BGC proliferation and increased BA production. Reducing edible oil use and increasing edible starch can mitigate the risk of BGC-related food poisoning in wet rice noodles and vermicelli production. Further research is needed to find alternative oils that do not enhance BA production. Strengthening prevention and control measures is crucial across the entire production chain to address BGC contamination and BA production.

Metabolic reprogramming in astrocytes results in neuronal dysfunction in intellectual disability.

Astrocyte aerobic glycolysis provides vital trophic support for central nervous system neurons. However, whether and how astrocytic metabolic dysregulation contributes to neuronal dysfunction in intellectual disability (ID) remain unclear. Here, we demonstrate a causal role for an ID-associated SNX27 mutation (R198W) in cognitive deficits involving reshaping astrocytic metabolism. We generated SNX27R196W (equivalent to human R198W) knock-in mice and found that they displayed deficits in synaptic function and learning behaviors. SNX27R196W resulted in attenuated astrocytic glucose uptake via GLUT1, leading to reduced lactate production and a switch from homeostatic to reactive astrocytes. Importantly, lactate supplementation or a ketogenic diet restored neuronal oxidative phosphorylation and reversed cognitive deficits in SNX27R196W mice. In summary, we illustrate a key role for astrocytic SNX27 in maintaining glucose supply and glycolysis and reveal that altered astrocytic metabolism disrupts the astrocyte-neuron interaction, which contributes to ID. Our work also suggests a feasible strategy for treating ID by restoring astrocytic metabolic function.

Trajectories of Perceived Stress among Students in Transition to College: Mindset Antecedents and Adjustment Outcomes.

There is growing evidence of a clear association between students' perceived stress and their adjustment to life at college. However, the predictors and implications of distinct changing patterns of perceived stress during the transition to college life are less clear. To address these research gaps, the current study aims to identify distinct patterns of perceived stress trajectories among 582 Chinese first-year college students (Mage = 18.11, SDage = 0.65; 69.40% female) across the first 6 months upon enrollment. Three distinct profiles of perceived stress trajectories, i.e., low-stable (15.63%), middle-decreasing (69.07%), and high-decreasing (15.29%), were identified. Moreover, individuals who followed the low-stable trajectory showed better distal outcomes (specifically, higher levels of well-being and academic adjustment) 8 months after enrollment than those who followed the other two trajectories. Furthermore, two types of positive mindset (a growth mindset of intelligence and a stress-is-enhancing mindset) contributed to differences in perceived stress trajectory, either independently or jointly. These findings highlight the significance of identifying different patterns of perceived stress among students during the transition to college, as well as the protective roles of both a stress mindset and a mindset of intelligence.

The deubiquitinase USP6 affects memory and synaptic plasticity through modulating NMDA receptor stability.

Ubiquitin-specific protease (USP) 6 is a hominoid deubiquitinating enzyme previously implicated in intellectual disability and autism spectrum disorder. Although these findings link USP6 to higher brain function, potential roles for USP6 in cognition have not been investigated. Here, we report that USP6 is highly expressed in induced human neurons and that neuron-specific expression of USP6 enhances learning and memory in a transgenic mouse model. Similarly, USP6 expression regulates N-methyl-D-aspartate-type glutamate receptor (NMDAR)-dependent long-term potentiation and long-term depression in USP6 transgenic mouse hippocampi. Proteomic characterization of transgenic USP6 mouse cortex reveals attenuated NMDAR ubiquitination, with concomitant elevation in NMDAR expression, stability, and cell surface distribution with USP6 overexpression. USP6 positively modulates GluN1 expression in transfected cells, and USP6 down-regulation impedes focal GluN1 distribution at postsynaptic densities and impairs synaptic function in neurons derived from human embryonic stem cells. Together, these results indicate that USP6 enhances NMDAR stability to promote synaptic function and cognition.

Human Papillomavirus Prevalence and Integration Status in Tissue Samples of Bladder Cancer in the Chinese Population.

BACKGROUND: Human papillomavirus (HPV) infection is associated with multiple types of cancer, but the evidence has not yet been fully elucidated in bladder cancer. METHODS: Frozen tissue samples collected from 146 patients aged 32 to 89 years with bladder cancer pathological diagnosis between 2015 and 2019 were analyzed. HPV genotyping and integration status determination were performed by capture-based next generation sequencing. Statistical analysis of HPV type distributions was performed according to stage, grade, sex, and age group of patients. RESULTS: Mean (SD) age of the 146 patients was 66.64 ±â€…10.06 years and 83.56% were men. Overall HPV infection rate was 28.77% (37.50% in women and 27.05% in men), with 11.90% HPV integration events. Among them, 17.12% single and 11.65% coinfections were observed. HPV18 (24.66%) was the most prevalent genotype, followed by HPV33, 16, and 39. All HPV were European lineage (A). HPV16 was more prevalent in women (P = .04). CONCLUSIONS: HPV infection may contribute to the etiology both in men and women with bladder cancer. HPV18, followed by HPV33, 16, and 39 genotypes, potentially represent the predominant oncogenic risk types for bladder carcinogenesis.

Associations between trait and state perceived stress and daily moods: COVID-19 stressful experiences as a moderator.

Drastically disrupting daily routines, the global pandemic of COVID-19 has posed critical mental health threats to adolescents and young adults worldwide. Many of the extant empirical findings, however, have focused on individuals' psychological adjustment during the initial phase of the pandemic. It is less clear how COVID-19 stressful experiences impact young people's daily lives in the post-pandemic "new normal." Drawing on 7-day diary reports, the present study fills this gap by examining: (1) how daily perceived stress impacted daily emotional adjustment; and (2) the moderating effects of COVID-19 stressful experiences on these associations among 582 Chinese young adults (M age = 18.12, SD = .65; 69% females). Results indicated that higher levels of both trait (i.e., average levels) and state (i.e., daily fluctuations) perceived stress were associated with greater negative and anxious moods, and that prior pandemic-related experiences exacerbated the adverse impact of both trait and state perceived stress on daily moods. Specifically, young adults reporting greater COVID-19 stressful experiences demonstrated poorer emotional adjustment (i.e., lower levels of positive mood and higher levels of negative mood) on days when they had more fluctuations in perceived stress; the aggravating impact was stronger when the average levels of perceived stress were higher. By illuminating the moderating effects of COVID-19 stressful experiences, this study contributes to the limited, but burgeoning, research examining the prolonged impact of the COVID-19 health crisis on daily emotional adjustment in post-pandemic life.

Evaluation of the effects of an artificial intelligence system on endoscopy quality and preliminary testing of its performance in detecting early gastric cancer: a randomized controlled trial.

BACKGROUND: Esophagogastroduodenoscopy (EGD) is a prerequisite for detecting upper gastrointestinal lesions especially early gastric cancer (EGC). An artificial intelligence system has been shown to monitor blind spots during EGD. In this study, we updated the system (ENDOANGEL), verified its effectiveness in improving endoscopy quality, and pretested its performance in detecting EGC in a multicenter randomized controlled trial. METHODS: ENDOANGEL was developed using deep convolutional neural networks and deep reinforcement learning. Patients undergoing EGD in five hospitals were randomly assigned to the ENDOANGEL-assisted group or to a control group without use of ENDOANGEL. The primary outcome was the number of blind spots. Secondary outcomes included performance of ENDOANGEL in predicting EGC in a clinical setting. RESULTS: 1050 patients were randomized, and 498 and 504 patients in the ENDOANGEL and control groups, respectively, were analyzed. Compared with the control group, the ENDOANGEL group had fewer blind spots (mean 5.38 [standard deviation (SD) 4.32] vs. 9.82 [SD 4.98]; P < 0.001) and longer inspection time (5.40 [SD 3.82] vs. 4.38 [SD 3.91] minutes; P < 0.001). In the ENDOANGEL group, 196 gastric lesions with pathological results were identified. ENDOANGEL correctly predicted all three EGCs (one mucosal carcinoma and two high grade neoplasias) and two advanced gastric cancers, with a per-lesion accuracy of 84.7 %, sensitivity of 100 %, and specificity of 84.3 % for detecting gastric cancer. CONCLUSIONS: In this multicenter study, ENDOANGEL was an effective and robust system to improve the quality of EGD and has the potential to detect EGC in real time.

High Yield Poly(ethylene-alt-maleic acid) Grafting to Wood Pulp while Minimizing Fiber/Fiber Wet Adhesion.

Heating bleached kraft pulps treated with poly(ethylene-alt-maleic acid) (PEMAc) can lead to high yields of carboxylated polymer grafted to fibers. However, in many cases, the cured, dry pulp cannot be effectively repulped (redispersed in water) because the wet strength is too high. Impregnation with PEMAc solutions at pH 4 followed by high temperature (120-180 °C), catalyst-free curing for short times can give fixation yields >85% while maintaining repulpability. The combination of high fixation yields with low wet strength is possible because the extent of curing required for high grafting yields is less than the curing requirement for high wet strength. Two challenges in moving this technology to practicable applications are (1) identifying the optimum laboratory pulp curing conditions and (2) translating laboratory curing conditions to industrial processes. A modeling tool was developed to meet these challenges. The model is based on the observation that for curing conditions giving high fixation yields the wet tensile indices of grafted pulp sheets showed a power-law dependence on the ßΓ product where ß is the conversion of the succinic acid moieties in PEMAc to the corresponding succinic anhydride groups in the curing step and Γ is the amount of polymer applied to the pulp. For two PEMAc molecular weights and two pulp types, the power-law slopes were 0.6; however, the pre-exponential terms depended upon the specific polymer and pulp type combination. We propose that the relationships between the wet tensile index and ßΓ, from polymer-treated, laboratory pulp handsheets, can be used to predict if proposed curing conditions for larger-scale processes will produce a repulpable product.

Inhibiting MAPK14 showed anti-prolactinoma effect.

BACKGROUND: The specific underlying pathogenesis of prolactinoma has not been clarified yet, to the best of our knowledge. p38 mitogen-activated protein kinase (MAPK) signaling including p38α MAPK (MAPK14), p38ß (MAPK11), p38γ (MAPK12) and p38δ (MAPK13) is associated with the development and progression of several types of cancer. METHODS: Immunofluorescence analysis was performed on the prolactin (PRL) and MAPK14 expressions of pituitary gland in C57BL/6 mice and human prolactinoma specimen. In the present study, the role of MAPK14 in prolactinoma was determined using estradiol-induced mice and dopamine D2 receptor knockout (DRD2-/-) mice models in C57BL/6 wild-type (WT), MAPK14-/- and DRD2-/-MAPK14+/- mice. GH3 cells were transfected with different sets of MAPK14 small interfering RNA, which to study MAPK14 and PRL expression in GH3 cells. RESULTS: Immunofluorescence analysis showed that PRL and MAPK14 expression were colocalized and increased in the pituitary gland of mice and human prolactinoma specimen compared with the control specimen. It was shown that PRL and MAPK14 expression was colocalized and increased significantly in the pituitary gland of estradiol-injected prolactinoma mice compared with the control mice. Knockout of MAPK14 significantly inhibited tumor overgrowth, and PRL expression was decreased in estradiol-induced mice. Furthermore, MAPK14 knockout of DRD2-/-MAPK14+/- mice significantly reduced the overgrowth of pituitary gland and PRL production and secretion compared with DRD2-/- mice. MAPK14 knockout using siRNA inhibited PRL production in GH3 cells. CONCLUSION: These results suggest that MAPK14 serves a promoting role in the formation of prolactinoma, and highlights the potential of MAPK14 as a potential therapeutic target in the treatment of prolactinoma.

Enhanced Antitumor Efficacy of Curcumin-Loaded PLGA Nanoparticles Coated with Unique Fungal Hydrophobin.

Modifications to the surface chemistry, charge, and hydrophilicity/hydrophobicity of nanoparticles are applicable approaches to the alterations of the in vivo fate of intravenously administered nano-sized drug carriers. The objective of this study is to investigate the in vitro and in vivo antitumor efficacies of curcumin PLGA nanoparticles in relation to their surface structural modification via self-assembling coating with unique fungal hydrophobin. The hydophobin-coated curcumin PLGA nanoparticles (HPB PLGA NPs) were obtained by simply soaking curcumin-loaded PLGA nanoparticles (PLGA NPs) in aqueous fungal hydrophobin solution. The in vitro drug release behavior of the HPB PLGA NPS was also tested. The cytotoxicity and cellular uptake of these nanoparticles were determined in HepG2, A549, and Hela cell lines using MTT assay method and CLSM observation. The in vivo antitumor activity was evaluated in Hela tumor xenografted mice model. Compared with the PLGA NPs, the size and zeta potential of the nanoparticles were changed after hydrophobin coating, whereas similar in vitro release pattern was observed. The pharmacodynamics study showed prolonged blood retention of both nano-formulations than that of free curcumin, but no significant difference between the hydrophobin coated and uncoated nanoparticles. It was found that HPB PLGA NPs had increased cytotoxicities, higher cellular uptake, and improved antitumor efficacy. Surface modification of nanoparticles via self-assembling of hydrophobin is a convenient and promising method of changing particle surface physiochemical properties and antitumor performances. Further investigations, especially on tissue distribution, were needed to assess the potential application of the hydrophobin self-assembling coating in nano-drug delivery carriers.

Coexpression network analysis of platelet genes in sickle cell disease.

Platelets play important roles in vascular health. Activation of platelet may contribute to coagulation and inflammation. Evidence suggests circulating platelets are chronically activated in sickle cell disease (SCD) patients with steady state and further activated in vaso-occlusive crisis. However, the molecular basis of sickle platelet dysfunction remains obscure. Here, we used weighted gene coexpression network analysis combined with differentially expressed genes (DEGs) analysis to further investigate this basis. We found 57 DEGs were closely related to platelet dysfunction in SCD. Enrichment analysis showed that these 57 genes were mostly related to protein synthesis, adenosine triphosphate (ATP) synthase activity and inflammation, suggesting a hyperactivation status of platelets in SCD. We identified six hub genes from the 57 DEGs according to their Gene Significance value ranking, including CRYM, CCT6P1, SUCNR1, PRKAB2, GSTM3 and FCGR2C. Altogether, our results offered some new insight into platelet activation and identified novel potential targets for antiplatelet therapy in SCD.

Dual silencing of EGFR and HER2 enhances the sensitivity of gastric cancer cells to gefitinib.

Gefitinib exhibits very limited efficacy in gastric cancer (GC). Indeed, the limited clinical results obtained with gefitinib alone justify investigation of additional therapeutic strategies. Here, we demonstrate the importance of EGFR and HER2 in GC malignancy using RNA interference (RNAi). Additionally, we explored the ability of RNAi targeting EGFR and HER2 to enhance the sensitivity of GC cells to gefitinib. Specific small interfering RNAs (siRNAs) significantly inhibited mRNA and protein expression of target genes. EGFR-specific siRNA, EGFR/HER2 siRNAs, and gefitinib inhibited growth and induced apoptosis in GC cell lines in a dose-dependent manner. In contrast, resistance to HER2-siRNA-induced growth inhibition and apoptosis was linked to compensatory activation of EGFR. Moreover, gefitinib dramatically reduced p-EGFR and p-HER2 levels in the cell lines tested, and sensitivity to gefitinib was enhanced through dual silencing of EGFR and HER2 via suppression of AKT and ERK activation. These findings are in agreement with the profound inhibitory effect of gefitinib on activation of both EGFR and HER2. Overall, EGFR/HER2 knockdown by siRNAs further decreased the growth of GC cells treated with gefitinib alone, confirming that single-agent drug targeting does not achieve a maximal biological effect. The combination of gefitinib with EGFR/HER2 siRNAs should be further investigated as a new strategy for the treatment of GC and other EGFR/HER2-dependent cancers.

Lentivirus-mediated knockdown of FcγRI (CD64) attenuated lupus nephritis via inhibition of NF-κB regulating NLRP3 inflammasome activation in MRL/lpr mice.

Lupus nephritis, one of the most serious complications of systemic lupus erythematosus (SLE), has been confirmed in a large number of clinical surveys. Current studies have suggested that inflammatory situation is generally considered to facilitate the occurrence and development of lupus nephritis. Previous research found that Fcγ receptor I (FcγRI) was compulsory for several autoimmune and inflammatory diseases, and it might be involved in the treatment of lupus nephritis. Furthermore, the possible molecular mechanism of the role of FcγRI in lupus nephritis still needs a further study. In the present study, in order to evaluate the effect of FcγRI on kidney function in lupus-prone MLR/lpr mice, FcγRI knockdown was implemented utilizing FcγRI-RNAi lentivirus. We reported that the administration of FcγRI-RNAi lentivirus (1) mainly inhibited FcγRI expression on macrophage of the kidneys, lowered the levels of urinary protein and serum anti-dsDNA antibody and prevented the impairment of renal function; (2) reduced the renal inflammatory cytokines (IL-1ß and IL-18); (3) decreased NF-κB p65 nuclear migration, suppressed NOD-like receptor protein 3 (NLRP3) inflammasome activation, and finally inhibited renal inflammation. Together, these results showed the role of FcγRI on macrophages to involve in renal inflammatory response, potentially via regulating the NLRP3 inflammasome-associated signaling.

Salvianolic acid A attenuates kidney injury and inflammation by inhibiting NF-κB and p38 MAPK signaling pathways in 5/6 nephrectomized rats.

Salvianolic acid A (SAA) is a minor phenolic carboxylic acid extracted from Salviae miltiorrhizae Bunge (Danshen). SAA exhibits a variety of pharmacological activities, such as antioxidative, anti-thrombotic, neuroprotective, and anti-fibrotic effects, as well as protection from myocardial ischemia and prevention of diabetes and other diseases. Furthermore, SAA has shown renal-protective effects in doxorubicin-induced nephropathy. However, there has been limited research regarding the effects of SAA and underlying mechanisms in chronic kidney disease (CKD). Here, we examined the effects and molecular mechanisms of SAA in an established animal model of 5/6 nephrectomized (5/6Nx) rats. The rats were injected with SAA (2.5, 5, and 10 mg/kg per day, intraperitoneally (ip)) for 28 days. SAA dose-dependently lowered the levels of urine protein, blood urea nitrogen, serum creatinine, plasma total cholesterol, and plasma triglycerides in 5/6Nx rats. Histological examination revealed that SAA dose-dependently attenuated renal pathological lesions, evidenced by reduced renal tubulointerstitial fibrosis by decreasing the expression levels of tumor growth factor-ß1 and α-smooth muscle actin in 5/6Nx rats. Moreover, SAA dose-dependently inhibited the activation of nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, subsequently attenuating the secretion of tumor necrosis factor-α and interleukin-1ß and inhibiting the expression of monocyte chemotactic protein-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in kidneys of 5/6Nx rats. The above results were consistent with those obtained in lipopolysaccharide-induced HK-2 cells in vitro (a recognized in vitro inflammatory model). In conclusion, our results demonstrated that SAA effectively attenuates kidney injury in 5/6Nx rats. The therapeutic effects of SAA on kidney injury can be attributed to its anti-inflammatory activities through inhibition of the activation of the NF-κB and p38 MAPK signaling pathways.

The Role of the Oxytocin/Arginine Vasopressin System in Animal Models of Autism Spectrum Disorder.

The nonapeptides oxytocin (OXT) and arginine vasopressin (AVP) are two key mediators in regulating various aspects of mammalian social behaviours. There are several lines of evidence that genetic variants of the OXT/AVP system exist in autism spectrum disorder (ASD) and that this system is dysfunctional at least in some ASD entities. These findings have stimulated the interest to perform studies testing the potential therapeutic application of OXT/AVP in ASD. In this respect animal models are critical for investigating the pathophysiology and for compound screening leading to new therapeutic approaches. Based on findings in animal models that show alterations of the OXT/AVP system, it has been hypothesised that single- or multiple-dose administration or the stimulation of endogenous release can improve several social deficits. Here we comprehensively review the role of the OXT/AVP system in social recognition, social interaction and maternal behaviour in the light of different ASD animal models and patient studies. We further discuss implications for OXT/AVP-related pharmacological interventions to alleviate social deficits in ASD in the future.

TNFR1 and TNFR2 differentially mediate TNF-α-induced inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes.

TNF-α has long been implicated in the progression of rheumatoid arthritis (RA). However, how the receptors of TNF-α, namely TNFR1 and TNFR2, mediate TNF-α-induced inflammatory responses in fibroblast-like synoviocytes (FLS) in RA has not been elucidated. In the present study, primary FLS cells were isolated from RA patients and treated with TNF-α in vitro. The exogenous TNF-α induced the expression and release of endogenous TNF-α in FLS. In addition, TNF-α led to gradual downregulation of TNFR1 following 1 h treatment. By contrast, the expression of TNFR2 was markedly upregulated after 12 h treatment with TNF-α. Moreover, following TNF-α treatment, the expression of interleukin (IL)-2, IL-6, and IL-8 was gradually increased with time, but their mRNA levels dropped significantly at 48 h. We further investigated the differential functions of TNFR1 and TNFR2 in FLS by conducting siRNA-mediated knockdown. The TNF-α autocrine was inhibited to a greater extent in TNFR1-silenced FLS compared with TNFR2-silenced FLS. Silencing of TNFR1, not TNFR2, activated intrinsic apoptosis and inhibited TNF-α-induced cytokine production in FLS. These results suggest that TNFR1 is the major pro-inflammatory mediator of TNF-α in FLS, whereas TNFR2, which is upregulated in response to prolonged TNF-α stimulation, may act as an immunosuppressor in FLS for the prevention of overwhelming inflammatory reactions.