Enhanced Production Of TNF-α Research Articles

The possible role of tumor necrosis factor-alpha in diabetic polyneuropathy.

In this review, the authors provide evidences that imply the role of tumor necrosis factor-α (TNF-α) in the pathogenesis of diabetic complications, especially diabetic polyneuropathy. Under chronic hyperglycemia, endogenous TNF-α production is accelerated in microvascular and neural tissues, which may undergo an increased microvascular permeability, hypercoagulability, and nerve damage, thus initiating and promoting the development of characteristic lesions of diabetic microangiopathy and polyneuropathy. Enhanced TNF-α production may also promote atherosclerosis due to increased insulin resistance and the expression of adhesion molecules. Clinical application of specific agents that suppress production and/or activity of TNF-α may inhibit the development and exacerbation of chronic diabetic complications.

Enhanced TNFα production by monocytic-like cells exposed to dengue virus antigens

The studies indicating the importance of TNFα in dengue virus infection have led us to determine whether monocyte-like cells produce TNFα after exposure to dengue virus. The supernatant fluids of mosquito cells (AP61) infected with dengue virus (DV) type 1 and DV type 3 were harvested 7 days post-infection and clarified. DV inactivation was performed in the presence of betapropiolactone that preserves antigenicity of viruses. We used the monocytic-like cell line THP-1 that is a model system of TNFα production. Polymyxin B (50 μg/ml) was added to block untoward effects resulting from possible LPS contamination of media or cultures. THP-1 cells were primed with a phorbol ester (PMA) for 24 h, then they were cultured for 4 and 24 h in the presence of inactivated culture supernatant of dengue infected AP61 cells or control preparations. The concentrations of TNFα in the culture supernatants were measured by using an immunoenzymatic assay. PMA-treated THP-1 cells rapidly secreted TNFα in response to inactivated culture supernatant of DV-infected cells. We found high levels of TNFα with cells exposed to DV1 and DV3 preparations compared with controls (mean values; 465 and 829 vs. 70 pg/ml, respectively, at 24 h post exposure, n = 4). We obtained a substantial inhibition of the enhancing activity of DV1 and DV3 infected supernatants in the presence of dengue hyperimmune mouse ascitic fluids. Our results demonstrate that exposure of monocytes/macrophages to DV particles or virus proteins derived from DV may be responsible for the enhanced production of TNFα in DV-infected patients.

The immunomodulatory activity of peptides related to the DNA contacting loop of p53 protein.

Taking into account the sequence homology existing between thymopoietin II and the DNA-binding domain of p53 protein, a series of octapeptides was synthesized, related to the wild p53 type protein as well as to its mutated forms, appearing in some human tumours. The wild type octapeptide has immunostimulative activity with regard to the humoral immune response, but is inactive in the cellular immune response. The mutated peptides of p53 differ in their immunomodulatory activity from the wild type octapeptide. The Ser5 analogue of the wild peptide is a strong stimulant of the humoral immune response and enhances TNF-alpha production, while at the same time suppressing the cellular immune response. The data suggest that the mutations of p53, which favour tumour development and growth, may also change the immune activity of respective p53 fragments.

Inducer-Specific Bidirectional Regulation by Thalidomide and Phenylphthalimides of Tumor Necrosis Factor-α Production

Regulation by thalidomide [N(α)-phthalimidoglutarimide] of tumor necrosis factor (TNF)-α production was found to be inducer-specific. Thalidomide enhances TNF-α production by human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while it inhibits TNF-α production induced with okadaic acid (OA) in the same cell line. Some phthalimide analogs, including PP-33 [2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione] and its 4,5,6,7-tetrafluoro derivative (FPP-33), also showed such an inducer-specific bidirectional TNF-α production-regulating activity. The structure–activity relationships of the compounds tested are similar, but not identical, in the TPA-stimulated HL-60 and OA-stimulated HL-60 assay systems.

Augmented Production of Tumor Necrosis Factor-α in Obese Mice

Non-insulin-dependent diabetes mellitus develops in obesity. The insulin resistance of this disease may be mediated by tumor necrosis factor-α (TNF-α). In particular, the TNF-α derived from adipose tissues might be involved in the induction of peripheral insulin resistance in rodent models of obesity. In general, monocytes/macrophages have been considered as the major source of TNF-α. This study was designed to examine the potential production of TNF-α from monocyte/macrophages in obese mice. In obese ( ob/ob) and obese diabetic ( db/db) mice, both of which are known to have severe insulin resistance, unstimulated serum bioactivity of TNF-α was significantly higher than that in lean control mice. Spontaneous TNF-α mRNA expression in splenic macrophages was also enhanced in obese mice, but not in monosodium- l-glutamate (MSG)-induced obese mice which have no insulin resistance. In addition, both ob/ob and db/db mice produce more TNF-α than lean mice upon in vivo lipopolysaccharide (LPS) stimulation. The LPS-induced increase in serum TNF-α activity was not observed in MSG-induced obese mice. Taken together, it is postulated that TNF-α produced by monocytes/macrophages may also play an important role in the genesis of insulin resistance in obesity. Further study is needed to reveal the mechanism of enhanced TNF-α production in obese states and its possible etiologic relevance to obesity.

Macrophage activation by lipopolysaccharide, interferon‐γ and interleukin‐4: effect of fatty acid metabolism

The aim of this study was to investigate the effects of interferon-γ and -β (IFN-γ, -β), interleukin-4 and -10 (IL-4, -10) and Hpopolysaccharide (LPS) on the metabolism and composition of phospholipid fatty acids in macrophages. Murine J774.2 macrophages were incubated with radiolabelled fatty acids and the appropriate stimulus and the incorporation and composition of the phospholipid classes was determined. IFN-γ and IL-4 specifically stimulated enhanced incorporation of [14C]-linoleic acid into the phosphatidytethanolamine fraction. IL-4 (in contrast to IFN-γ and LPS) reduced incorporation of [14C]- arachidonic acid into phosphatidylinositol. Incubation of J774.2 cells with linoleic acid significantly increased TNFα and nitric oxide production; arachidonic acid enhanced TNFα production but reduced nitric oxide production. It is concluded that IFN-γ, IL-4 and IL-10 may differentially regulate macrophage activation via effects on the metabolism of polyunsaturated fatty acids.

Mechanisms of allogeneic stimulation induced tumor necrosis factor-α (TNF-α) production

We investigated the mechanisms of allogeneic stimulation induced TNF-α production in vitro by using human peripheral blood mononuclear cells (PBMC) and Daudi lymphoblastoid B-cells. PBMC produced TNF-α in response to mitomycin C-treated or paraformaldehyde-fixed Daudi cells, reaching a peak level after 4–6 h of culture. Monocytes were identified as the major source of TNF-α produced during allogeneic cell interaction. The second potent producer of TNF-α was E-rosette non-forming natural killer cells. Purified T-cells did not produce significant levels of TNF-α, even in the presence of IL-1 and IL-6. Interleukin-4 (IL-4) down-regulated TNF-α production by monocytes, but in contrast interferon-γ (IFN-γ) moderately enhanced TNF-α production. Our results indicate that monocytes are mainly responsible for the production of TNF-α in response to allogeneic stimulation, and T-cells modulate monocyte function by their soluble factors.