Anti-tumor necrosis factor α therapy associates to type 17 helper T lymphocytes immunological shift and significant microbial changes in dextran sodium sulphate colitis

BACKGROUND Anti-tumor necrosis factor α(TNFα) represents the best therapeutic option to induce mucosal healing and clinical remission in patients with moderate-severe ulcerative colitis. On the other side gut microbiota plays a crucial role in pathogenesis of ulcerative colitis but few information exists on how microbiota changes following anti-TNFα therapy and on microbiota role in mucosal healing.AIM To elucidate whether gut microbiota and immune system changes appear following anti TNFα therapy during dextran sulfate sodium(DSS) colitis.METHODS Eighty C57 BL/6 mice were divided into four groups: "No DSS", "No DSS + antiTNFα", "DSS" and "DSS + anti-TNFα". "DSS" and "DSS + anti-TNFα" were treated for 5 d with 3% DSS. At day 3, mice whithin "No DSS+anti-TNFα" and"DSS+anti-TNFα" group received 5 mg/kg of an anti-TNFα agent. Forty mice were sacrificed at day 5, forty at day 12, after one week of recovery post DSS. The severity of colitis was assessed by a clinical score(Disease Activity Index), colon length and histology. Bacteria such as Bacteroides, Clostridiaceae, Enterococcaceae and Fecalibacterium prausnitzii(F. prausnitzii) were evaluated by quantitative PCR.Type 1 helper T lymphocytes(Th1), type 17 helper T lymphocytes(Th17) and CD4+ regulatory T lymphocytes(Treg) distributions in the mesenteric lymph node(MLN) were studied by flow cytometry.RESULTS Bacteria associated with a healthy state(i.e., such as Bacteroides, Clostridiaceae and F. prausnitzii) decreased during colitis and increased in course of anti-TNFαtreatment. Conversely, microorganisms belonging to Enterococcaceae genera,which are linked to inflammatory processes, showed an opposite trend.Furthermore, in colitic mice treated with anti-TNFα microbial changes were associated with an initial increase(day 5 of the colitis) in Treg cells and a consequent decrease(day 12 post DSS) in Th1 and Th17 frequency cells. Healthy mice treated with anti-TNFα showed the same histological, microbial and immune features of untreated colitic mice. "No DSS + anti-TNFα" group showed a lymphomononuclear infiltrate both at 5 th and 12 th d at hematoxylin and eosin staining, an increase of in Th1 and Th17 frequency at day 12, an increase of Enterococcaceae at day 5, a decrease of Bacteroides and Clostridiaceae at day 12.CONCLUSION Anti-TNFα treatment in experimental model of colitis improves disease activity but it is associated to an increase in Th17 pathway together with gut microbiota alteration.

Real-life outcome of anti-tumor necrosis factor α in the ambulatory treatment of ulcerative colitis

AIM:To evaluate the outcome of anti-tumor necrosis factor alpha(anti-TNFα) therapy in outpatients with ulcerative colitis at a tertiary referral center.METHODS:All patients with a confirmed diagnosis of ulcerative colitis undergoing therapy with infliximab and/or adalimumab at the outpatient clinic for inflammatory bowel diseases at the University Hospital Heidelberg between January 2011 and February 2014 were retrospectively enrolled.Patients with a followup period of less than 6 mo from start of anti-TNFα therapy were excluded.Medical records of all eligible individuals were carefully reviewed.Steroid-free clinical remission of a duration of at least 3 mo,colectomy rate,duration of anti-TNFα therapy,need for anti-TNFα dose escalation,and the occurrence of adverse events were evaluated as the main outcome parameters.RESULTS:Seventy-two patients were included(35 treated with infliximab,17 with adalimumab,20 with both consecutively).Median follow-up was 27 mo(range:6-87 mo).Steroid-free clinical remission was achieved by 22.2% of the patients(median duration:21 mo until end of follow-up; range:3-66 mo).Patients attaining steroid-free clinical remission displayed lower hemoglobin and albumin blood levels at the start of treatment than those who did not achieve remission.The overall colectomy rate was 20.8%.Nearly 50% of the patients underwent anti-TNFα dose escalation during the follow-up period.For both the infliximab and the adalimumab treated patients,non-response to anti-TNFα therapy was the major reason for treatment discontinuation.18.2% of the infliximab-treated patients and 13.5% of the adalimumab-treated patients had to discontinue their therapy due to adverse events.CONCLUSION:Real-life remission rates of ulcerative colitis under anti-TNFα are overall low,but some patients have a clear long-term benefit.

Perioperative Use of Methotrexate and Tumor Necrosis Factor α Inhibitors Combination Therapy Is Not Likely to Increase Post-Operative Infection Rate in the National Veterans Health Administration Administrative Databases

Objective: The aim of the study is to assess the risk of post-operative outcome in rheumatoid arthritis (RA) patients continuing versus stopping combination therapy of methotrexate (MTX) and hydroxychloroquine (HCQ) or tumor necrosis factor α inhibitors (TNF) prior to surgery. Methods: Using the United States Veterans Affairs (VA) databases, we identified surgical procedures in a 17-year cohort of RA patients. Among those patients, those on MTX + HCQ or MTX + TNF were identified. Post-operative outcome variables include infection, length of post-operative hospital stay and death. Results: We identified a total of 29,708 surgeries in RA patients. Among them, we identified the most recent elective surgeries without pre-operative infection in 16,174 patients. There were 783 and 550 patients on MTX + HCQ and MTX + TNF, respectively. The rates of post-op infection were 5% and 4% for the MTX + HCQ and MTX + TNF continuing medication groups, respectively, similar to the general RA population (5%). Sensitivity analyses at various time points of discontinuation combination therapies prior to surgery did not show significant change in terms of infection. Conclusions: The prevalence of adverse outcome is low. The proportion of post-operative infection in continuing and discontinuing medicine groups is similar for both MTX + HCQ and MTX + TNF. While we were unable to formally compare proportions of post-operative infection among the two groups, these preliminary findings do not support the hypothesis that continuing either MTX + TNF or MTX + HCQ combination during perioperative period increases post-operative infection compared with discontinuation prior to therapy.

Inhibitory Actions of Tetrandrine on Tumor Necrosis Factor α-Induced NF-κB Activation in Neovascularization of Cultured Choroidal Explants

Tetrandrine (1 μM), a bis-benzylisoquinoline alkaloid isolated from Stephania tetrandra S Moore, signifi-cantly decreased tumor necrosis factor alpha (TNFα;10 ng/ml)-induced increase in the number of micro vessels that budded from cultured rat choroidal explants. Tetrandrine also decreased the TNFα-induced in-crease in the number of cells composing the microvessels. Ammonium pyrrolidine dithiocarbamate (APDC;0.1-0.3 μM), an inhibitor of nuclear factor-κB (NF-κB), decreased the TNFα-induced increase in the number of microvessels in a concentration-dependent manner. TNFα increased the phosphorylation and degradation of inhibitor of NF-κB (IκBα), as well as increasing the DNA-binding activity of NF-κB in choroidal explants. TNF? induced an increase of vascular endothelial growth factor (VEGF)-A mRNA, but not VEGF-C mRNA or VEGF-D mRNA. TNFα-induced angiogenic action was inhibited by treatment of VEGF-A antibody in cultured choroidal capillaries. Tetrandrine inhibited the TNFα-induced increases of phosphorylation and degradation of IκBα, and reduced the TNFα-induced increase of DNA-binding activity of NF-κB in chor-oidal explants. In conclusion, tetrandrine inhibits TNFα-induced activation of NF-κB in the choroidal capil-laries via inhibition of TNFα-induced phosphorylation of IκBα.

Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.

The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice

Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.

Treatment of primary nasal tuberculosis with anti-tumor necrosis factor immunotherapy:A case report

BACKGROUND Primary nasal tuberculosis(TB)is a rare form of extrapulmonary TB,particularly in patients receiving anti-tumor necrosis factor(TNF)immunotherapy.As a result,its diagnosis remains challenging.CASE SUMMARY A 58-year-old male patient presented to the ear,nose,and throat department with right-sided nasal obstruction and bloody discharge for 1 month.He was diagnosed with psoriatic arthritis and received anti-TNF immunotherapy for 3 years prior to presentation.Biopsy findings revealed chronic granulomatous inammation and a few acid-fast bacilli,suggestive of primary nasal TB.He was referred to our TB management department for treatment with oral anti-TB agents.After 9 months,the nasal lesions had disappeared.No recurrence was noted during follow-up.CONCLUSION The diagnosis of primary nasal TB should be considered in patients receiving TNF antagonists who exhibit thickening and crusting of the nasal septum mucosa or inferior turbinate,particularly when pathological findings suggest granulomatous inflammation.

Early screening to identify and diagnose primary nasal tuberculosis in patients with tumor necrosis factor inhibitors

In this editorial,we comment on the article by Liu et al.Based on our analysis of a case report,we consider that early screening and recognition of primary nasal tuberculosis are crucial for patients undergoing treatment with tumor necrosis factor inhibitor(TNFi).While TNFi therapy increases the risk of reactivating latent tuberculosis,primary nasal tuberculosis remains rare due to the protective mechanisms of the nasal mucosa.Risk factors for primary nasal tuberculosis include minimally invasive nasal surgery,diabetes,and human immunodefi ciency virus.Patients with early symptoms such as nasal congestion,rhinorrhea,altered olfaction,epistaxis,or ulceration,and unresponsive to conventional antibiotics and antihistamines should undergo early rhinoscopy,possibly followed by repeated tissue biopsies and acid-fast bacilli culture when necessary.When diagnosis is challenging,it is essential to consider local tuberculosis epidemiology and the efficacy of diagnostic antituberculosis treatment.The preferred method for tuberculosis screening is the Interferon Gamma Release Assay,with a general recommendation for screening at 3 and 6 months after initial treatment and then every six months.However,the optimal frequency is not yet consensus-driven and may be increased in economically viable settings.

Analyze interleukin-1β,interleukin-6,and tumor necrosis factor-αlevels in dry eye and the therapeutic effect of cyclosporine A

BACKGROUND Dry eye is a common eye disease.Artificial tears supplements are widely used for the treatment of dry eyes.However,multiple adverse effects have been observed in patients receiving long-term treatment with artificial tears,which may affect the therapeutic effect.AIM To analyze the characteristics of interleukin-1β(IL-1β),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α)levels in patients with dry eye and the therapeutic effect of artificial tears combined with cyclosporine A.METHODS A total of 124 dry eye patients treated at The First People’s Hospital of Xining from April 2020 to April 2022 were selected as the observation group,while 20 healthy individuals served as the control group during the same period.Levels of inflammatory markers,including IL-1β,IL-6,and TNF-α,were analyzed.The observation group was further divided into a study group and a control group,each consisting of 62 patients.The control group received artificial tears,whereas the study group received a combination of artificial tears and cyclosporine A.Inflammatory markers,Schirmer’s test(SIT),tear break-up time(TBUT),corneal fluorescein staining(CFS),National Eye Institute Visual Function Questionnaire-25(NEI-VFQ-25)scores,and adverse events(AEs)were compared between the two groups.RESULTS The observation group exhibited significantly elevated serum levels of IL-1β,IL-6,and TNF-αin comparison to the healthy group.Following treatment,the study group demonstrated substantial reductions in IL-1β,IL-6,and TNF-αlevels relative to the control group.Moreover,after treatment,the study group experienced a marked decrease in CFS scores and significant increases in both SIT and BUT levels when compared to the control group.Additionally,significant improvements were observed in the primary symptom of dry eye and secondary symptoms such as photophobia,foreign body sensation,fatigue,red eye,and burning sensation within the study group.Furthermore,post-treatment NEI-VFQ-25 scores across all dimensions exhibited significant enhancements in the study group compared to the control group(P<0.05).It is noteworthy that significant AEs were reported in both groups throughout the treatment period.CONCLUSION Cyclosporine A combined with artificial tears is effective in treating dry eye,yielding enhanced outcomes by improving SIT and TBUT levels,reducing CFS scores,and ameliorating vision-related quality of life.

Efficacy of Laparoscopic Cholecystectomy in Treating Patients with Gallstones and Its Effect on Interleukin-6 and Tumor Necrosis Factor-α Levels

Objective:To investigate the efficacy of laparoscopic cholecystectomy in the treatment of patients with gallstones and its effect on the levels of interleukin-6(IL-6)and tumor necrosis factor-α(TNF-a).Methods:A total of 82 patients with gallstones admitted from July 2020 to July 2023 were recruited and allocated into control and observation groups using the random number table method,with 41 cases in each group.The patients were treated with laparoscopic cholecystectomy,with the anterior triangle anatomical approach to the gallbladder in the control group and the posterior triangle anatomical approach to the gallbladder in the observation group.The treatment effect and inflammatory factor levels of both groups were observed and compared.Results:When comparing the clinical outcomes of both patient groups,the key parameters evaluated included time to mobilization,duration of surgery,extubation time,and intraoperative bleeding.The observation group exhibited a significant advantage in these parameters compared to the control group(P<0.05).Regarding the levels of inflammatory factors between the two groups before and after treatment,there was no significant difference in values before treatment.However,following treatment,patients in the observation group showed significantly lower levels of IL-6,TNF-α,and C-reactive protein(CRP)compared to the control group(P<0.05).Conclusion:Patients undergoing laparoscopic cholecystectomy for gallstones can benefit from the implementation of the posterior triangular anatomical approach to the gallbladder,which not only enhances therapeutic efficacy but also offers significant advantages in reducing levels of IL-6,TNF-α,and CRP.Therefore,it is recommended for the widespread adoption of this treatment approach in clinical practice.

Effects of Acupuncture at Baihui(DU20) and Zusanli(ST36) on the Expression of Heat Shock Protein 70 and Tumor Necrosis Factor α in the Peripheral Serum of Cerebral Ischemia-Reperfusion-Injured Rats

Objective： To explore the effects of acupuncture on the peripheral serum expression of heat shock protein 70 （HSP70） and tumor necrosis factor a （TNF-α ） in rats with cerebral ischemia-reperfusion injury （CIRI）. Methods： In total, 152 Sprague-Dawley （SD） rats were randomly divided into an operated group and a non-operated group according to a random digits table. The operated group included a sham-operated group, a model group and an acupuncture group, whereas the non-operated group consisted of a normal group. Except for the normal group, each group was further divided into 12, 24, 48, 72, 96, and 144 h time points according to different reperfusion times. Eight rats were assigned in each operated group and in the normal group. The rat model of CIRI was established by the thread occlusion method in the model and acupuncture groups. The acupuncture group was treated with electroacupuncture at Baihui （DU20） and Zusanli （ST36） for the required time after successful operation. Blood was sampled to detect the HSP70 and TNF- o~ content by enzyme linked immunosorbent assay. Results： The expression of HSP70 protein in the peripheral serum of the experimental groups was higher than that in the normal control group. The peak time in both the model and the sham-operated groups was 12 h, and the peak time in the acupuncture group was 24 h. The expression in the acupuncture group declined to a lower level at 72 h and was lower than that in the model and sham-operated groups （P〈0.05）. The peak time for the expression of TNF-α protein in the peripheral serum of both the model and the acupuncture groups was 24 h, but the expression in the acupuncture group was lower than the model group. Additionally, the expression of TNF- o~ in all experimental groups was higher than the normal group （P〈0.05）. Conclusions： Acupuncture at DU20 and ST36 in rats attenuated CIRI, which was associated with a reduction in the expression of HSP70 and TNF-a. These results provide clues to acupuncture＇s neuroprotective properties. Acupuncture at DU20 and ST36 in rats after CIRI can adjust the expression of HSP70 and TNF- ~ in the peripheral serum, which might be one of the mechanisms of acupuncture＇s attenuation of CIRI.

Recombination Mutant Human Tumor Necrosis Factor Combined with Chemotherapy in the Treatment of Advanced Cancer

Objective: Past studies showed that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. The objective of present study is to evaluate the therapeutic effects and adverse reactions of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy in patients with advanced malignant tumor. Methods: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients. rmhTNF was injected intramuscularly to the trial group at a dose of 4×106 U/m2, from the 1st to 7th days, the 11th to 17th days combined with chemotherapy course. The chemotherapy plan was as follows: CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. Results: In the trial group there was 1 CR case and 12 PR cases, and the response rate was 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate in the trial group was significantly higher than that in the control group (P=0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those in the control groups. After the treatment the KPS was 89.00±9.92 in the trial group, and 84.17±8.84 in the control group, with a significant difference between the two groups (P=0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable. Conclusion: The administration of rmhTNF in combination with general chemotherapy is an effective and secure means in treating advanced malignant tumor.

Interleukin-1β,Tumor Necrosis Factor-α and Lipopolysaccharide Induce Expression of Monocyte Chemoattractant Protein-1 in Calf Aortic Smooth Muscle Cells

Summary: To investigate whether interleukin-1β(IL-1β), tumor necrosis factor-α (TNF-α) and lipopolysaccharide (LPS) induce expression of monocyte chemoattractant protein-1 (MCP-1 ) mRNA and protein in calf aortic smooth muscle cells(SMCs), calf aortic SMCs were cultured by a substrate-attached explant method. The cultured SMCs were used between the third to the fifth passage. After the cells became confluent, the SMCs were exposed to 2 ng/ml IL-1β, 20ng/ml TNF-1α and 100 ng/ml LPS respectively, and the total RNA of SMCs which were incubated for 4 h at 37℃ were extracted from the cells by using guanidinium isothiocyanate method. The expres- ion of MCP-1 mRNA in SMCs was detected by using dot blotting analysis using a probe of γ-32 P- end-labelled 35-mer oligonucleotide. After a 24-h incubation, the media conditioned by the cul- tured SMCs were collected. The MCP-1 protein content in the conditioned media was determined by using sandwich ELISA. The results were as follows: Dot blotting analysis showed that the cul- tured SMCs could express MCP-1 mRNA. After a 4-h exposure to IL-1β, TNF-α and LPS, the MCP-1 mRNA expression in SMCs was increased (3.6-fold, 2. 3-fold and 1. 6-fold, respectively). ELISA showed that the levels of MCP-1 protein in the conditioned media were also increased (2.9- fold, 1.7-fold and 1.1-fold, respectively). The results suggest that calf aortic SMCs could ex- press MCP-1 mRNA and protein. IL-1β and TNF-α can induce strong expression of MCP-1 mRNA and protein, and the former is more effective than the latter.

High circulating N-terminal pro-brain natriuretic peptide and tumor necrosis factor-α in mixed cryoglobulinemia

AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor α (TNF-α) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV).METHODS: Serum NTproBNP and TNF-α levels were assayed in 50 patients with MC+HCV, and in 50 sex- and age-matched controls. RESULTS: Cryoglobulinemic patients showed signifi cantly higher mean NTproBNP and TNF-α levels than controls (P < 0.001; Mann-Whitney U test). By defining high NTproBNP level as a value higher than 125 pg/mL (the single cut-off point for outpatients under 75 years of age), 30% of MC+HCV and 6% of controls had high NTproBNP (χ2, P < 0.01). With a cut-off point of 300 pg/mL (used to rule out heart failure (HF) in patients under 75 years of age), 8% of MC+HCV and 0 controls had high NTproBNP (χ2, P < 0.04). With a cut-off point of 900 pg/mL (used for ruling in HF in patients aged 50-75 years; such as thepatients of our study), 6% of MC+HCV and 0 controls had high NTproBNP (χ2, P = 0.08).CONCLUSION: The study demonstrates high levels of circulating NTproBNP and TNF-α in MC+HCV patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunction.

Uptake of bacterial lipopolysaccharide and expression of tumor necrosis factor α mRNA in isolated rat intrahepatic bile duct epithelial cells *

AIM To study the uptake of bacterial lipopolysaccharides (LPS) and expression of tumor necrosis factor α mRNA (TNF α mRNA) with cultured rat intrahepatic bile duct epithelial cells.

Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

Anti-tumor necrosis factor(TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases(IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn's disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each antiTNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membranebound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with antiTNF antibodies in chronic intestinal inflammation, by predicting response to therapy.

Changes of interleukin-1β, tumor necrosis factor α and interleukin-6 in brain and plasma after brain injury in rats

Objective: To study the changes of interleukin 1 β (IL 1β), tumor necrosis factor α (TNFα) and interleukin 6 (IL 6) levels in brain and plasma after brain injury and to assess the relationship between the cytokine levels and injury severity in rats. Methods: A total of 51 male Wistar rats, weighing 280 340 g , were anesthetized with chloral hydrate ( 400 mg/kg body weight) through intraperitoneal injection and fixed on a stereotaxic instrument. Severe brain injury was created in 16 rats (severe injury group) and moderate brain injury in 18 rats (moderate injury group) by a fluid percussion model, and cytokine levels of IL 1β, TNFα and IL 6 were measured with biological assay. And sham operation was made on the other 17 rats (control group). Results: In the control group, the levels of IL 1β, TNFα and IL 6 were hardly detected in the cortex of the rats, but in the ipsilateral cortex of the rats in both injury groups, they increased obviously at 8 hours after injury. The increasing degree of these cytokines had no significant difference between the two injury groups. The levels of IL 6 in the plasma of all the rats increased slightly, whereas the levels of IL 1β and TNFα were undetectable. Conclusions: The increase of IL 1β, TNFα and IL 6 levels is closely related to brain injury. The increased cytokine levels in the central nervous system are not parallel to those in the peripheral blood. It suggests that inflammatory cytokines play important roles in the secondary neural damage after brain injury.

Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis

AIM: To evaluate the role of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cirrhotic patients who have hepatic and renal impairment with spontaneous bacterial peritonitis (SBP).

Anti Cervix Cancer Activity of Co-immobilized Tumor Necrosis Factor-α and Interferon-γ

Tumor necrosis factor α （TNF-α） and interferon-γ （IFN-γ） are cytokines with strong antitumor activities. They were reacted with a photoactive arylazide-4-azidobenzoic acid, resulting in photoactive TNF-α and IFN-γ. The infrared （IR） spectra of these products showed the characteristic absorption of an azido group at 2127 cm^-1. By photo-immobilization, this modified TNF-α and IFN-γ were immobilized on polystyrene membranes for cell culture to prepare biomaterials. The micro-morphology of photoactive cytokines was observed with a scanning electron microscope （SEM）. The inhibitory effect on growth of Hela cells and inducing apoptosis activity of these two cytokines were analyzed by growth curve, transmission electron microscope （TEM） and fluorescence active cell sorter （FACS）. The results showed that co-immobilization of IFN-γ and TNF-α had significant inhibitory effect on growth of Hela cells, inhibitory rate up to 82%, and IFN-γ had obviously synergistic action.

TUMOR NECROSIS FACTOR-ALPHA POLYMORPHISM AND SECRETION IN MYASTHENIA GRAVIS

Objective To analyze the relationship between tumor necrosis factor-alpha (TNFα) gene promoter -308 polymorphism and myasthenia gravis (MG) in Chinese and analyze secretion of TNFα in peripheral blood mononuclear cells (PBMC) in MG patients. Methods A biallelic polymorphism at position -308 in the promoter of TNFα gene was screened by PCR amplification and NcoI recognition site. One hundred and twenty-three MG cases and 115 healthy controls were included in this study. MG patients were classified to different groups according to clinical type, age at onset, and sex respectively. PBMC were isolated from 20 patients and 20 healthy controls, and then cultured in the presence or absence of phytohemag- glutinin (PHA) and acetycholine receptors (AchR). The supernatants were harvested after incubation and stored until TNFα was assayed by enzyme-linked immunosorbent assay. Results The frequency of TNFα-308 allele 2 (A) was found significantly increase in MG patients and showed a trend especially in late onset (≥ 40 years) and male patients (P < 0.05). The allele A had no relationship with thymic pathogenesis in MG patients. But frequency of allele A was significantly higher in general type than in ocular type (P < 0.05). MG patients had a higher inducible level of TNFα by PHA and AchR, and could be down regulated after treatment. Conclusion Polymorphism in TNFα gene promoter -308 is associated with onset of MG. The microsatellite allele TNFα2 confer risk for the development of MG in Chinese patients. MG patients have a higher inducible level of TNFα.