Disease relevance of Tnf

• We demonstrate that Sh3bp2 "cherubism" mice exhibit trabecular bone loss, TNF-alpha-dependent systemic inflammation, and cortical bone erosion [1].
• Neutralizing antibodies to TNFalpha and IL-1beta protect AUF1 knockout mice against lethal endotoxic shock [2].
• Excessive production of proinflammatory cytokines, particularly tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta), plays a critical role in septic shock induced by bacterial endotoxin (endotoxemia) [2].
• A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency [3].
• Tumor necrosis factor (TNF)-related cytokines regulate cell death and survival and provide strong selective pressures for viruses, such as cytomegalovirus (CMV), to evolve counterstrategies in order to persist in immune-competent hosts [4].
• Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning [5].
• These observations identify TNF-alpha as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-alpha may be useful in treating colon cancer in individuals with UC [6].

Psychiatry related information on Tnf

• Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption [7].
• We have previously shown that TNF-alpha up-regulated the expression of formyl peptide receptor 2 (mFPR2) in mouse microglial cells, resulting in increased chemotactic responses of such cells to mFPR2 agonists, including amyloid beta1-42 (Abeta42), a critical pathogenic agent in Alzheimer's disease [8].
• The results of this study suggest that the cytokines IFN-gamma and TNF-alpha as well as the integrins Mac-1 and VLA-4 are involved in protective cellular host defense mechanisms in PP and MLN against Y. enterocolitica, the latter probably being involved in both cell-cell and cell-pathogen interactions [9].
• This effect is antagonized by tumor necrosis factor-alpha, a pro-inflammatory cytokine putatively involved in dementia and aging [10].
• The collective findings of TNF-alpha overexpression during the course of clinical disease suggest that TNF-alpha may mediate the myelin sheath vacuolation observed in experimental CJD [11].

High impact information on Tnf

• () now demonstrate that a cherubism mutation activates mouse Sh3bp2 resulting in enhanced production of the cytokine TNF-alpha by myeloid cells, leading to both bone loss and inflammation [12].
• Critically, identity of a JNK substrate that promotes TNFalpha-induced apoptosis has been outstanding [13].
• Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response [14].
• TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death [14].
• Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration [14].

Chemical compound and disease context of Tnf

• Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone [15].
• We show that the genes for tumor necrosis factor alpha and granzyme A, a serine protease associated with cytoplasmic granules of cytotoxic cells, are expressed during the development of spontaneous diabetes mellitus in the nonobese diabetic mouse [16].
• A similar requirement for dectin-1 in TNF-alpha production was observed for macrophages infected with M bovis Bacillus Calmette-Guerin (BCG), M phlei, M avium 2151-rough, and M tuberculosis H37Ra [17].
• D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor alpha (TNF-alpha) plays a pivotal role [18].
• Transmembrane TNFalpha transgenic mice were fully protected from endotoxic shock, and no TNFalpha bioactivity was detectable in the serum after stimulation with lipopolysaccharide [19].

Biological context of Tnf

• Among the compound mutants, only the Tnf (-/-) K19-C2mE mice showed significant suppression of hyperplastic tumors with reduced cell proliferation [20].
• These findings indicate distinct but also overlapping roles of Tnfr1 and Tnfr2 in primary mouse fibroblasts and suggest different regulation mechanisms of signal transduction pathways under the control of both Tnf receptors [21].
• A JNK-dependent pathway is required for TNFalpha-induced apoptosis [22].
• An essential role for NF-kappaB in preventing TNF-alpha-induced cell death [23].
• Treatment of young TTP-deficient mice with antibodies to tumor necrosis factor alpha (TNF alpha) prevented the development of essentially all aspects of the phenotype [3].

Genetic context of TNF

• Serum level of TNFα in mice infected by Leishmania major is influenced by loci Lmr12 (chromosome 16), Lmr13 (chromosome 18), Lmr14 (chromosome 2) and Lmr17 (chromosome 9) [24]

Anatomical context of Tnf

• In conclusion, the combined inactivation of Tnf and Ltalpha confirms their essential role in the normal development and function of the immune system [25].
• Subcellular fractionation of LPS-stimulated macrophages revealed that LPS signals transduced by Tpl2 specifically promote the transport of TNF-alpha mRNA from the nucleus to the cytoplasm [26].
• TNF-alpha induced MnSOD mRNA in all cell lines and normal cells examined in vitro and in various organs of mice in vivo [27].
• Of the proapoptotic challenges tested, K17-null skin keratinocytes in primary culture are selectively more sensitive to TNFalpha [28].
• Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion [28].

Associations of Tnf with chemical compounds

• Tumor-necrosis factor (TNF), a pleiotropic cytokine, triggers physiological and pathological responses in several organs [29].
• Tpl2 knockout mice produce low levels of TNF-alpha when exposed to lipopolysaccharide (LPS) and they are resistant to LPS/D-Galactosamine-induced pathology [26].
• These effects of TNF-alpha and IL-1 on target cells may contribute to their reported protective activity against radiation as well as their ability to induce resistance to cell killing induced by the combination of TNF-alpha and cycloheximide [27].
• In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-alpha and IL-6, but not of lactate or nitric oxide [30].
• Tartrate-resistant acid phosphatase-positive osteoclasts were also formed when M-BMM phi were further cultured for 3 d with mouse tumor necrosis factor alpha (TNF-alpha) in the presence of M-CSF [31].
• By the use of HIF-1-deficient cells and by obliterating NF-kappaB activation, it was determined that the hypoxic TACE response is mediated by HIF-1 signaling, whereas the regulation by TNFalpha also requires NF-kappaB activation [32].
• Activation of the protein kinase C pathway by treatment with phorbol ester, which has been shown previously to result in CUGBP1 phosphorylation, also causes TNF mRNA stabilization [33].
• PDTC accelerated death and aggravated liver apoptosis in the GalN/LPS model, although it reduced nitric oxide production, attenuated glutathione depletion, and inhibited the expression of TNF-alpha in liver [34].
• CcO isolated after TNFalpha treatment showed tyrosine phosphorylation on CcO catalytic subunit I and was approximately 50 and 70% inhibited at high cytochrome c concentrations in the presence of allosteric activator ADP and inhibitor ATP, respectively [35].
• Accordingly, c-Flip(L/S) protein levels were elevated in livers of TNFalpha-tolerant mice, which correlated to a switch from JNK and ERK to p38 signaling after galactosamine/TNF re-challenge [36].
• In BDL mice, cardiac mRNA and protein expression of NFkappaBp65, p38MAPK, iNOS, NOx, anandamide, and plasma TNFa were increased, whereas glutathione, Cu/Zn-SOD, and Mn-SOD were decreased [37].

Physical interactions of Tnf

• Following its induction, TNFalpha gene transcription is rapidly attenuated, in part due to the accumulation of NF-kappaB p50 homodimers that bind to three kappaB sites in the TNFalpha promoter [38].
• Furthermore, RA inhibited activator protein-1 binding to 12-O-tetradecanoylphorbol 13-acetate-response element (TRE) in the cells treated with TNF-alpha, suggesting that RA acts as a potent negative regulator for activator protein-1 binding activity to TRE in the osteoblastic cells [39].
• We also found that LPL caused the nuclear migration of one member of the NFkB family that appears to bind to a site in the murine TNF alpha gene promoter [40].
• Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases [41].
• It efficiently antagonizes the effect of TNF-alpha binding to the TNF receptor (I) [42].
• Using chromatin immunoprecipitation assays, we demonstrated that treatment of adipocytes with TNFalpha led to increased binding of NFkappaB p50, and decreased binding of p65 and Sp1, to this region of the apoE promoter in living cells [43].

Enzymatic interactions of Tnf

• Jo2 and, to a lesser extent, TNF-alpha phosphorylate Akt [44].
• Collectively, these findings suggest that pp130 and pp95 are constitutively associated with CD120a (p55) and become inducibly phosphorylated in macrophages in response to TNFalpha [45].
• Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure [46].
• Western blot analyses showed significantly increased levels of TNF-alpha (1.8-fold) and phosphorylated-SAPK/JNK1/2 (1.5-fold) in transgenic hearts [47].
• Here we demonstrate that Ser311 accounts for zetaPKC phosphorylation of RelA and that this site is phosphorylated in vivo in response to TNF-alpha [48].

Co-localisations of Tnf

• Western blot analysis of MAdCAM-1 purified by affinity column chromatography from TNF-alpha-treated bEnd.3 cells demonstrates a 66-kDa protein that comigrates in SDS-PAGE with the MAdCAM-1 constitutively found on high endothelial venules in murine mesenteric lymph nodes [49].

Regulatory relationships of Tnf

• These results indicate a role for TTP in regulating TNF alpha synthesis, secretion, turnover, or action [3].
• IL-4 inhibited immunoglobulin E-induced TNF-alpha production and neutrophil recruitment in the peritoneal cavity in wild-type mice but not in signal transducers and activators of transcription 6 (Stat6)-deficient mice [50].
• Surface plasmon resonance studies showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-alpha-induced activity bound to RANK ligand (RANKL) [51].
• Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha [52].
• NF-kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis [53].
• Further, co-transfection with either dominant negative Egr-1 or the IkappaB super-repressor prevented gAcrp-stimulated TNF-alpha promoter activity. gAcrp also increased Egr-1 promoter activity, mRNA accumulation, and DNA binding activity [54].
• Small interfering RNA-mediated knockdown of beta-arrestin-1 inhibits TNFalpha-induced tyrosine phosphorylation of G alpha(q/11) by interruption of Src kinase activation [55].
• We found that the resistance to TNF-alpha-induced apoptosis observed in ANT3 mutant (ANT3(mut)) cells is associated with a deficiency in the regulation of the mitochondrial membrane potential and cytochrome c release [56].
• TNF-alpha induced ROS-dependent genetic instability in Fancc-/- but not in WT cells [57].
• Hence, TNFalpha promotes myoblast proliferation through JNK1 and prevents myoblast differentiation through JNK1-mediated secretion of LIF [58].
• Herein, we describe a novel neuron-intrinsic pathway in which the expression of the type-1 inositol 1,4,5-trisphosphate receptor is regulated by the potent pro-inflammatory cytokine tumor necrosis factor-alpha [59].

Other interactions of Tnf

• Export of tumor necrosis factor-alpha and interleukin-6 (IL-6) from these cells was also diminished [60].
• Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin [61].
• The greatly reduced capacity of BCG-infected IFN-gamma R0/0 mice to produce TNF-alpha may be an important factor in their inability to resist BCG infection [62].
• Moreover, the patients' blood and fibroblastic cells responded to other NF-kappaB activators, such as tumor necrosis factor-alpha, IL-1beta, and lipopolysaccharide [63].
• The protective effect of IL-10 was reversed by prior injection of neutralizing anti-IL-10 antibodies, and correlated with a substantial decrease in endotoxin-induced TNF-alpha release [64].
• TNF-alpha/TNFR1-mediated signals on APCs and TNF-alpha/TNFR2 signals on T cells were critically required for effective priming, proliferation, and recruitment of tumor-specific T cells [65].

Analytical, diagnostic and therapeutic context of Tnf

• In this study we have analysed the effect of ablating cytokine production in two mouse models of arthritis: collagen-induced arthritis (CIA) in DBA/1J mice and the inflammatory polyarthritis of tumor necrosis factor alpha (TNF-alpha) transgenic mice [66].
• Unexpectedly, the lack of TNF alpha led to a significant delay in remyelination as assessed by histology, immunohistochemistry for myelin proteins and electron microscopy coupled with morphometric analysis [15].
• In addition, serum, kidney, and urine levels of TNF-alpha measured by ELISA were increased by cisplatin [67].
• To investigate the mechanisms underlying these findings, we examined levels of the cytokines IL-5, IL-4, and TNFalpha in both bronchoalveolar lavage (BAL) and serum [68].
• Biological assays and immunoassays demonstrate that PMN translate these mRNAs, except TNF-alpha, into secretory proteins [69].

References