Reduction of tumor necrosis factor α and interleukin-1β levels in human synovial tissue by interleukin-4 and glucocorticoid

Summary The effects of recombinant human interleukin-4 (IL-4) and the glucocorticoid, dexamethasone, on tumor necrosis factor (TNF) and interleukin-1 (IL-1) levels in cultures of rheumatoid and osteoarthritic synovial tissue were studied. Low concentrations of IL-4 and dexamethasone suppressed the levels of both cytokines in the supernatants of both types of tissue after stimulation with lipopolysaccharide (LPS); the IL-1 and TNF levels were measured by ELISA. It is suggested that it is the monocyte/macrophage in the synovial tissues that is responsive to the inhibitors. It is proposed that glucocorticoids may act on synovial tissue in this manner in vivo and IL-4 may do so if administered intraarticularly.     

Study on the association between tumor necrosis factor α gene polymorphism and systemic lupus erythematosus.

Objective: To examine whether polymorphism within the tumor necrosis factor α(TNFα) gene is associated with the susceptibility and clinic manifestations to systemic lupus erythe matosus (SLE) in the patients of Han ethnic group collected from the Northern China. Methods: TNF_1 and TNF_2 subtypes     

Evaluation of preoperative and postoperative serum interleukin-6, interleukin-8, tumor necrosis factor α and raftlin levels in patients with obstructive sleep apnea

Background

Raftlin is a large, major lipid raft protein of cell membranes. Raftlin levels have not been previously examined in patients with obstructive sleep apnea (OSA). Our study aimed to evaluate the changes in raftlin, interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNFα) values from the preoperative state to the third month postoperatively in patients undergoing expansion sphincter pharyngoplasty for OSA.

Methods

Of 60 patients, 10 patients had mild OSA (AHI 5–14), 10 moderate (AHI 15–29), 10 severe (AHI ≥ 30), and 30 with AHI < 5 formed a control group. Preoperatively and at 3 months post-operatively, IL-6, IL-8, TNFα, and raftlin values were measured.

Results

Preoperatively, mean raftlin levels were 914.4 ± 62.7 pg/mL for controls, 910.0 ± 42.5 pg/mL in mild, 1000.5 ± 63.3 pg/mL in moderate, and 1386.3 ± 101.4 pg/mL in severe groups, with moderate and severe groups significantly elevated compared to controls (p < 0.001). Preoperatively to 3 months post-operatively, raftlin levels decreased significantly in each OSA group (p < 0.05). Levels of IL-6, IL-8 and TNFα followed similar patterns at baseline and after surgical intervention.

Conclusions

Raftlin levels at the third postoperative month decreased significantly compared with preoperative levels in parallel with other markers of inflammation.

     

Correction to: Evaluation of preoperative and postoperative serum interleukin-6, interleukin-8, tumor necrosis factor α and raftlin levels in patients with obstructive sleep apnea

Sleep and Breathing - A Correction to this paper has been published: https://doi.org/10.1007/s11325-021-02317-z     

Suppression of interleukin-1β- and tumor necrosis factor-·-induced inflammatory responses by leukocytapheresis therapy in patients with ulcerative colitis

Background To elucidate the molecular mechanisms involved in the therapeutic effects of leukocytapheresis (LCAP), we investigated the alterations in the cytokine responses of peripheral blood mononuclear cells (PBMCs) before and after LCAP therapy in ulcerative colitis (UC) patients.Methods Twelve patients with UC who did not respond to steroid therapy were enrolled. Nine patients responded to LCAP therapy, but 3 patients did not show clinical improvement. PBMCs were isolated from peripheral venous blood obtained within 5min before and after the first and second session of LCAP treatment. Cells were stimulated with interleukin (IL)-1 and tumor necrosis factor (TNF)- for 24h, and the levels of secreted IL-8 and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA).Results LCAP induced a significant decrease in peripheral lymphocyte, monocyte, and platelet counts. IL-1- and TNF--induced IL-8 and IL-6 secretion was significantly decreased after the first and second LCAP treatments. These responses were associated with inhibitory effects on nuclear factor (NF)-B DNA-binding activity.Conclusions LCAP downregulates the IL-1- and TNF--induced inflammatory responses in PBMCs isolated from UC patients. The induction of hyporesponsiveness to proinflammatory cytokines may be an important factor mediating the clinical effects of LCAP in UC patients.     

Levels of circulating tumor necrosis factor α and interleukin-6 in patients with rheumatoid arthritis. relationship to serum levels of hyaluronan and antigenic keratan sulfate

Objective. To measure serum levels of tumor necrosis factor α (TNF α) and interleukin-6 (IL-6) in patients with rheumatoid arthritis (RA) and age-matched control subjects and to study how these correlate with serum levels of hyaluronan (HA) and antigenic keratan sulfate (KS) and other biochemical as well as clinical indicators of disease activity. Methods. Immunoassays were used to measure levels of TNFα, IL-6, HA, and antigenic KS in the serum of 35 patients with RA and a group of age- and sex-matched control subjects. Clinical disease activity in the RA group was assessed using the Lansbury index. Drug intake was recorded and the erythrocyte sedimentation rate, and levels of fibrinogen, creatinine, bilirubin, alkaline phosphatase, lactate dehydrogenase, and aminotransferase were measured. Results. Serum levels of TNFα, IL-6, and HA were significantly higher in the RA population than in the control group. In patients with RA, serum levels of HA correlated positively with serum levels of TNFα and with clinical joint scores, but only weakly with other laboratory parameters of inflammation. Serum levels of antigenic KS correlated negatively with levels of circulating TNFα, but much more weakly with other clinical and biochemical parameters of disease activity. Conclusion. These in vivo data support in vitro studies which have shown that TNFα is a potent stimulator of HA synthesis by synovial lining cells. The results strengthen the contention that serum HA may be a unique marker of synovial involvement and inflammation, rather than of only inflammation, in RA.     

Patient-specific approach to combination versus monotherapy with the use of antitumor necrosis factor α agents for inflammatory bowel disease

It is likely that the debate surrounding combination versus monotherapy will continue for the foreseeable future, because there will always be a risk-benefit ratio that must be taken into account with IBD therapy. However, because more studies now include a thoughtful approach with respect to concomitant IS therapy with inclusion of objective end points such as mucosal healing and drug pharmacokinetics, it is anticipated that this issue will become clearer over time, which will benefit patients and practitioners. The BRIDGe approach described in this review is a useful tool but must be taken in the context of the subjectivity of much of the analyzed data and the individual perspectives that influenced the results. It cannot in any way be interpreted as a clinical practice guideline or standard of care, but rather a tool that seeks to interpret and incorporate the available literature and, it is hoped, aid clinicians in making sense of the conflicting data in this area. The decision regarding the risks and benefits of combination therapy must be carefully weighed in each individual patient.     

A comparison of an interferon-gamma release assay and tuberculin skin test in refractory inflammatory disease patients screened for latent tuberculosis prior to the initiation of a first tumor necrosis factor α inhibitor

Treatment with TNFα inhibitors increases risk of reactivating a latent tuberculosis\infection (LTBI). Therefore screening, prior to therapy with TNFα inhibitors, has been recommended, even in low-endemic areas such as well-developed Western Europe countries. We evaluated interferon-gamma release assay (IGRA), as opposed to tuberculin skin test (TST), for detection of LTBI in refractory inflammatory disease patients prior to the initiation of a first TNFα inhibitor. In addition, we evaluated the impact of impaired cellular immunity on IGRA. Patients starting on TNFα inhibition were screened for LTBI by TST and IGRA (Quantiferon-TB Gold). Data on tuberculosis exposure and Bacillus Calmette–Guérin (BCG) vaccination were obtained. Cellular immunity was assessed by CD4⁺ T lymphocyte cell count. Nine out of 56 patients (16.1%) tested positive for LTBI. A concordant positive result was present in three patients with a medical history of tuberculosis exposure. Six patients with discordant test results had either: (1) a negative TST and positive IGRA in combination with a medical history of tuberculosis exposure (n = 1) or (2) a positive TST and negative IGRA in combination with BCG vaccination (n = 3) or a medical history of tuberculosis exposure (n = 2). CD4⁺ T lymphocyte cell counts were within normal limits, and no indeterminate results of IGRA were present. IGRA appears reliable for confirming TST and excluding a false positive TST (due to prior BCG vaccination) in this Dutch serie of patients. In addition, IGRA may detect one additional case of LTBI out of 56 patients that would otherwise be missed using solely TST. Immune suppression appears not to result significantly in lower CD4⁺ T lymphocyte cell counts and indeterminate results of IGRA, despite systemic corticosteroid treatment in half of the patients. Confirmation in larger studies, including assessment of cost-effectiveness, is required.     

High release of tumor necrosis factor α, interferon γ and interleukin-6 by adherent lymphokine-activated killer cells phenotypically derived from T cells

Summary Adherent lymphokine-activated killer cells (A-LAK) are highly potent cytotoxic cells, which are shown to be derived not only from natural killer (NK)/K cells but phenotypically also from T cells. The generation and phenotypical and functional characterisation of these T-cell-derived A-LAK are described. In contrast to non-adherent cells (NA-LAK) and unseparated LAK (UN-LAK), these mostly CD3⁺CD56⁺ CD8⁺ cells display a high degree of expansion following initial interleukin-2 (rIL-2) activation and further culturing in autologous conditioned medium. A comparison of cytotoxic activities of cultured cells reveals a significantly higher oncolytic ability of A-LAK cells against both K562 and Daudi cells than that of cultured controls of NA-LAK and UN-LAK. In addition, A-LAK are characterised by a marked endogenous cytokine release of interferon, tumour necrosis factor and IL-6 as well as by their shedding of p55 IL-2 receptor after exposure to IL-2. The results demonstrate A-LAK to be the lymphocyte subpopulation with the most cytotoxic activity and endogenous cytokine release after exposure to IL-2. The improvement of techniques for long-term cultures may be of interest for future therapeutic approaches.Abbreviations used A-LAK adherent, lymphokine-activated killer cells - NK natural killer - CTCM complete tissue-culture medium - IL-2 interleukin-2 - IFN interferony - MNC peripheral blood mononuclear cells - TNF tumour necrosis factor This work was supported by the grant 01GA8802 of the Bundesministerium für Forschung und Technologie (BMFT)     

The association of tumor necrosis factor α receptor 2 and tumor necrosis factor α with insulin resistance and the influence of adipose tissue biomarkers in humans

Tumor necrosis factor α (TNFα) is a proinflammatory adipokine hypothesized to link obesity with insulin resistance. Functional studies suggest that TNFα acts through pathways involving adipokines and fatty acids to induce insulin resistance. We tested the hypothesis that the association of measures of TNFα activity with insulin resistance is independent of obesity and adipose tissue biomarkers. We analyzed data from 2131 participants (without diabetes) of the Framingham Offspring Study examination 7. The outcome of interest was insulin resistance, measured using the homeostasis model assessment (HOMA-IR). Tumor necrosis factor α activity was measured by plasma tumor necrosis factor α receptor 2 (TNFr2) or TNFα; possible confounders included adipose tissue biomarkers (plasma adiponectin, resistin, and triglycerides). We used multivariable age- and sex-adjusted linear regression analyses to adjust for waist circumference and for biomarkers individually and simultaneously, and in biomarker-stratified (above and below median) models. We found that TNFr2 was positively associated with HOMA-IR (r = 0.21, P < .0001). In age- and sex-adjusted model, for each increase of 1 standard deviation of TNFr2 (SD = 746 pg/mL), the log (HOMA-IR) value was increased by 0.11 units (P < .0001). Adjustment for waist circumference reduced the TNFr2 β-coefficient (by about 45%), but the association between TNFr2 and HOMA-IR remained significant (P < .0001). Tumor necrosis factor α receptor 2 was still associated to HOMA-IR after adding adiponectin, resistin, and triglycerides (individually and simultaneously). We found similar associations with plasma levels of TNFα. We conclude that, in a representative community sample, measures of TNFα activity are associated with insulin resistance, even after accounting for central adiposity and other adipose tissue biomarkers.     

Correlation between the concentrations of tumor necrosis factor-α and the severity of disease in patients infected with Orientia tsutsugamushi

BackgroundPatients with tsutsugamushi disease sometimes die if they do not receive appropriate chemotherapy. This study measured the concentration of several cytokines both before and after the administration of tetracyclines, and evaluated the changes in cytokine levels in patient serum to investigate the relationship between serum levels of cytokines and disease severity.MethodsA total of nine patients were infected with Orientia tsutsugamushi. The diagnosis of tsutsugamushi disease was made using an indirect immunoperoxidase antibody test. The serum concentrations of cytokines were measured using enzyme-linked immunosorbent assays.ResultsThe levels of interleukin (IL)-10 (mean 71.7 pg/ml) and IL-12p40 (mean 588 pg/ml) were elevated in all patients in the acute phase, above the normal upper limits. Tumor necrosis factor-α (TNF-α) levels (mean 9.20 pg/ml) were elevated in 89% and interferon-γ (IFN-γ) levels (mean 41.0 pg/ml) in 44% of patients. The down-regulation of these overproduced cytokines was observed after chemotherapy. There was a significant correlation between the concentrations of TNF-α in the acute phase and the severity of disease (r = 0.918).ConclusionThe concentration of TNF-α may predict the severity of tsutsugamushi disease in the acute infectious phase.     

Effect of treatment with amifostine used as a single agent in patients with refractory anemia on clinical outcome and serum tumor necrosis factor α levels

2 /day three times per week followed by a 2-week interval. Since tumor necrosis factor (TNF)α is a main suppressive cytokine for hematopoiesis in RA patients, serum samples for analyzing endogenous levels of TNFα were collected prior to the study and after four treatment cycles. In three patients (21%), reduced transfusion requirement with prolongation of the transfusion interval from 4 weeks to 8 weeks (two patients) and 4 weeks to 6 weeks was seen. An increase in ANC from 400/μl to 2600/μl and 200/μl to 3400/μl was observed in two patients. Platelets increased from 129,000/μl to 277,000/μl in an additional patient. In one patient, disease progression from RA to RAEB was observed. Serum TNFα levels were increased in MDS patients compared with normal controls (18.8 pg/ml vs 9.1 pg/ml), and there was no change during the treatment with amifostine (17.5 pg/ml). In conclusion, treatment with amifostine as a single agent was of limited benefit in patients with RA. The serum TNFα levels were unchanged during treatment with amifostine in RA patients. Received: 29 July 1999 / Accepted: 10 October 1999     

Combining effects of polymorphism of tumor necrosis factor α 5′-flanking region and HLA-DRB1 on radiological progression in patients with rheumatoid arthritis

We examined whether polymorphisms upstream of the TNF-α gene (TNFA) were associated with the radiological progression of rheumatoid arthritis (RA). One hundred and twenty-three patients with early RA (disease duration <1 year) were enrolled in a prospective follow-up study. The laboratory findings (ESR, CRP, and RF) were evaluated every 2 months for 2 years. Radiological progression in hands/wrists and feet was evaluated every 6 months for 2 years using Larsen’s score. HLA-DRB1 genotype was determined by PCR-RFLP method. The genotypes for -1031, -863, and -857 single-nucleotide polymorphisms in the upstream 5′-flanking region of TNFA were determined by a PCR-preferential homoduplex formation assay in patients with RA and 265 healthy controls. Four TNFA alleles (U01, U02, U03, and U04) were identified. The frequency of individuals with U02 was significantly higher in patients than in controls (P = 0.0025). Radiographs of hands/wrists/feet were available for 72 patients after 1 year and for 73 patients after 2 years. When the HLA-DRB1 genotype was analyzed simultaneously, patients possessing U02 without an HLA-DRB1 shared epitope (SE) (U02+SE−) showed the lowest progression of Larsen’s score (12 months). There was no difference in the level of ESR, CRP, or RF at the first visit among U02+SE+, U02+SE−, U02−SE+, and U02−SE− groups. The combination of the polymorphism of the TNFA upstream promoter region and HLA-DRB1 allele was associated with radiological progression in the early stage of RA.     

Expression of the tumor necrosis factorα gene and early response genes by nodularin, a liver tumor promoter, in primary cultured rat hepatocytes

Nodularin is a new liver carcinogen possessing a potent tumor-promoting activity in rat liver, mediated through inhibition of protein phosphatases 1 and 2A, and a weak initiating activity. Since we previously reported evidence that nodularin up-regulated expression of the tumor necrosis factor gene (TNF) and early-response genes in rat liver after its i.p. administration, and since TNF had tumor-promoting activity in vitro, it is possible that TNF itself is involved in liver tumor promotion. We investigated whether hepatocytes themselves induce expression of theTNF gene and early-response genes in primary cultured rat hepatocytes treated with nodularin. Like nodularin, microcystin-LR, which is another liver tumor promoter belonging to the okadaic acid class, strongly inducedTNF gene expression in rat hepatocytes, as well as TNF release from those cells into the medium. On the other hand, 12-O-tetradecanoylphorbol-13-acetate, which has been reported to induce no tumor promotion in rat liver, induced no apparent expression of theTNF gene in primary cultured rat hepatocytes. As for the expression of early-response genes, 1 M nodularin or microcystin-LR induced expression of the c-jun, jun B,jun D, c-fos, fos B andfra-1 genes in the hepatocytes, and the expression of these genes was prolonged up to 24 h, suggesting mRNA stabilization induced by inhibition of protein phosphatases 1 and 2A. This paper presents new evidence that theTNF gene and early-response genes were expressed in hepatocytes treated with a liver tumor promoter.Abbreviations GST-P glutathioneS-transferase placental form - TNF tumor necrosis factor - GAPDH glyceraldehyde-3-phosphate dehydrogenase - SSC standard saline citrate - SDS sodium dodecyl sulfate - TPA 12-O-tetradecanoylphorbol-13-acetate     

Visceral fat decreased by long-term interdisciplinary lifestyle therapy correlated positively with interleukin-6 and tumor necrosis factor-α and negatively with adiponectin levels in obese adolescents

The purpose of this study was to assess the level of cytokine expression in correlation with visceral and subcutaneous fat in obese adolescents admitted to long-term interdisciplinary weight loss therapy. The study was a longitudinal clinical intervention of interdisciplinary therapy. Adolescents (18, aged 15-19 years) with body mass indexes greater than the 95th percentile were admitted and evaluated at baseline and again after 1 year of interdisciplinary therapy. Visceral and subcutaneous fat was analyzed by ultrasonography. Blood samples were collected to analyze tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and adiponectin concentrations that were measured by enzyme-linked immunosorbent assay. The most important finding in the present investigation is that the long-term interdisciplinary lifestyle therapy decreased visceral fat. Positive correlations between IL-6 levels and visceral fat (r = 0.42, P < .02) and TNF-α levels and visceral fat (r = 0.40, P < .05) were observed. Negative correlations between TNF-α levels and subcutaneous fat (r = −0.46, P < .01) and adiponectin levels and subcutaneous fat (r = −0.43, P < .03) were also observed. In addition, we found a positive correlation between TNF-α levels and the visceral to subcutaneous fat ratio (r = 0.42, P < .02) and a negative correlation between adiponectin level and the visceral to subcutaneous fat ratio (r = −0.69, P < .001). Despite the limitation of sample size, our results indicate that the observed massive weight loss (mainly visceral fat) was highly correlated with a decreased inflammatory state, suggesting that the interdisciplinary therapy was effective in decreasing inflammatory markers.