Elevated Expression Of TNF-alpha Research Articles

Lack of STAT6 enhances murine acute lung injury through NLRP3/p38 MAPK signaling pathway in macrophages

BackgroundSignal transducer and activator of transcription 6 (STAT6) is an intracelluar transcriotion factor and NLRP3 (Nod-like receptor containing a pyrin domain 3) is a component of NLRP3 inflammasome in pyroptotic cells. There was increased activation of STAT6 and expression of NLRP3 in mice with murine acute lung injury (ALI). However, it is unknown their roles in the development of murine ALI. We in this study, investigated the effects of STAT6 signaling on murine ALI and pyroptosis in STAT6 knock-out (KO) mice and macrophages.ResultsSTAT6 was activated in the lung tissues of mice 2 days after intratracheal treatmemt with 5 mg/kg LPS. Lack of STAT6 expression in KO mice induced more severe lung inflammation, associated with elevated neutrophil influx and expression of TNF-alpha, IL-6 and IL-1beta in the inflamed lung tissues. In addition, the expression of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), p-p38 MAPK (p38 mitogen-activated protein kinase) and ratio of LC3-II/I (microtubule-associated protein-1 light chain-3) was increased, accompanied with the increased polarization of Siglec-F(−) subtype macrophages in KO mice with ALI. Further studies in bone marrow-derived macrophages (BMDMs) revealed that lack of STAT6 increased the expression of NLRP3 and p-p38 MAPK, in association with elevated expression of TNF-alpha, IL-1beta and Calreticulin in LPS-treated KO BMDMs.ConclusionsLack of STAT6 exacerbated murine ALI through improving the expression of NLRP3 and activation of p38 MAPK in macrophages. STAT6 has an immune suppressive role in the development of ALI and would be a promising therapeutic target in the treatment of ALI and possibly among patients with acute respiratory distress syndrome (ARDS).

Human S100A8 and S100A9 activate phagocytes via Toll-like receptor 4 independent of RAGE

Endogenous Damage Associated Molecular Pattern (DAMP) proteins are known as important pro-inflammatory factors of the immune system, which are released during cellular stress. Recognition of DAMPs involves the multiligand Receptor for Advanced Glycation End products (RAGE) and Toll-like receptors (TLRs) in sensing not only Pathogen Associated Molecular Patterns (PAMPs) but also endogenous proteins. Members of the fast growing family of DAMP proteins are besides heat shock proteins, HMGB1 or defensins also some members of the family of S100 proteins, which promote inflammatory processes. It was claimed that RAGE is involved in almost all S100 protein activities. We here investigated the capacity of human S100A8 (MRP8, myeloid related protein 8) and human S100A9 (MRP14) on activation of human phagocytes. S100A8 and S100A9 form homodimers as well as heterodimers and belong to the S100 family of EF-hand calcium-binding proteins. Both proteins are the major cytoplasmic proteins of phagocytes and are released at sites of inflammation by activated or necrotic phagocytes. While human S100A8/S100A9-complexes did not show any phagocyte activation, S100A8 homodimers as well as S100A9 homodimers induce strong pro-inflammatory mechanisms in these cells. Human S100A9 induces intracellular translocation of MyD88 and activation of IRAK-1 as shown recently already for murine S100A8. Finally NF-kB activation results in elevated expression of TNF-alpha as well as other pro-inflammatory genes. In blocking experiments with TLR4-specific monoclonal antibodies we demonstrate that both S100 proteins specifically signals via TLR4 receptor complex on human phagocytes. Using TLR4/MD2/CD14 transfected HEK293 cells and RAGE transfected HEK293 cells we clearly can exclude the involvement of RAGE for at least these two S100 proteins. Our in vitro results could be further confirmed in vivo. Mice lacking S100A8/S100A9 are protected against abdominal sepsis induced by E. coli. Our present data clearly demonstrate the importance of TLR4 by which phagocytes promote their own activation via expression and secretion of endogenous ligands of this receptor.

Amelioration of insulin resistance in diabetic ob/ob mice by a new type of orally active insulin-mimetic vanadyl complex: bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) with VO(S(2)O(2)) coordination mode.

Recently, we have shown that a newly synthesized vanadyl complex, bis(1-oxy-2-pyridinethiolato)oxovanadium(IV), VO(opt)(2), is a potent orally active insulin-mimetic in treating streptozotocin-induced diabetes in rats, with long-term action. In the present study, the anti-diabetic effect of VO(opt)(2) and its mechanism in ob/ob mice, an obese non-insulin-dependent diabetes mellitus (NIDDM) animal model, was investigated. In ob/ob mice, 15-day oral treatment with VO(opt)(2) resulted in a dose-dependent decrease in the levels of glucose, insulin and triglyceride in blood. VO(opt)(2) was also effective in ameliorating impaired glucose tolerance in ob/ob mice, when an oral glucose tolerance test was performed after treatment with VO(opt)(2). Tumor necrosis factor-alpha (TNF-alpha) is a key component of obesity-diabetes link, we therefore examined the attenuating effect of VO(opt)(2) on impaired insulin signal transduction induced by TNF-alpha. Elevated expression of TNF-alpha was observed in the epididymal and subcutaneous fat tissues of ob/ob mice. Incubation of 3T3-L1, mouse adipocytes, with TNF-alpha reduced the phosphorylation of insulin receptor substrate-1 (IRS-1), whereas VO(opt)(2) treatment resulted in an enhancement of IRS-1 phosphorylation, irrespective of the presence or absence of TNF-alpha. Overall, the present study demonstrates that VO(opt)(2) exerts an anti-diabetic effect in ob/ob mice by ameliorating impaired glucose tolerance, and furthermore, attenuates the TNF-alpha-induced decrease in IRS-1 phosphorylation in adipocytes. These results suggest that the anti-diabetic action of VO(opt)(2) is derived from an attenuation of a TNF-alpha induced impaired insulin signal transduction via inhibition of protein tyrosine phosphatase, providing a potential clinical utility for VO(opt)(2) in the treatment of NIDDM.

Tumor necrosis factor-alpha induces neuronal death by silencing survival signals generated by the type I insulin-like growth factor receptor.

Within the central nervous system, the proinflammatory cytokine tumor necrosis factor (TNF)-alpha is best characterized by its ability to directly foment signals of death. However, recent evidence suggests that TNF-alpha also promotes neurodegeneration through inhibition of a vital survival signal, insulin-like growth factor-I (IGF-I). By inhibiting essential components of the IGF-I survival response, such as phosphatidylinositol 3'-kinase (PI 3-kinase), low nontoxic concentrations of TNF-alpha indirectly trigger the death of neurons. We suggest that this inhibition of survival signaling is a pathophysiologically relevant action of TNF-alpha in the brain. This type of cross-talk by which vastly different receptors utilize shared intracellular substrates is potentially applicable to a broad number of receptors that are coexpressed on the same cell. The use of neuronal growth factors in the treatment of neurodegenerative diseases, such as cerebral ischemia and the AIDS dementia complex, may prove much more effective if the elevated expression of TNF-alpha in these disorders is neutralized.