Alternative titles; symbols
HGNC Approved Gene Symbol: TNF
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,575,565-31,578,336 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | {Asthma, susceptibility to} | 600807 | Autosomal dominant | 3 |
| {Dementia, vascular, susceptibility to} | 3 | |||
| {Malaria, cerebral, susceptibility to} | 611162 | 3 | ||
| {Migraine without aura, susceptibility to} | 157300 | Autosomal dominant | 3 | |
| {Septic shock, susceptibility to} | 3 |
Tumor necrosis factor (TNF) is a multifunctional proinflammatory cytokine secreted predominantly by monocytes/macrophages that has effects on lipid metabolism, coagulation, insulin resistance, and endothelial function. TNF was originally identified in mouse serum after injection with Mycobacterium bovis strain bacillus Calmette-Guerin (BCG) and endotoxin. Serum from such animals was cytotoxic or cytostatic to a number of mouse and human transformed cell lines and produced hemorrhagic necrosis and in some instances complete regression of certain transplanted tumors in mice (Shirai et al., 1985; Pennica et al., 1984).
Pennica et al. (1984) identified a monocyte-like human cell line that provided a source of TNF and its messenger RNA. cDNA clones were isolated, sequenced, and translated in E. coli. TNF and LTA (153440), or TNFB, have similar biologic activities and share 30% amino acid homology.
Wang et al. (1985) and Shirai et al. (1985) independently cloned cDNA sequences corresponding to the human TNF gene. The deduced 233-amino acid protein has a long leader sequence of 76 residues. The gene was expressed in E. coli, and the protein product produced necrosis of murine tumors in vivo.
TNF is synthesized as a 26-kD membrane-bound protein (pro-TNF) that is cleaved by processing enzymes (see, e.g., ADAM17; 603639 and Black et al., 1997) to release a soluble 17-kD TNF molecule The soluble molecule can then bind to its main receptors TNFR1 (191190) and TNFR2 (191191) (Skoog et al., 1999).
Aggarwal et al. (1985) presented evidence that TNF-alpha and TNF-beta share a common receptor on tumor cells and that the receptors are upregulated by gamma-interferon. Various interferons have been known to be synergistic with TNF in antitumor effects in vitro. Brenner et al. (1989) demonstrated that TNFA stimulates prolonged activation of the oncogene JUN expression; the JUN gene (165160) encodes transcription factor AP-1, which stimulates collagenase gene transcription. Thus, activation of JUN and collagenase gene expression may be one mechanism for mediating some of the biologic effects of TNFA.
Obeid et al. (1993) found that the intracellular concentration of ceramide increased by 45% at 10 minutes after the addition of TNF-alpha to cells in vivo. Treatment of cells with ceramide directly induced DNA fragmentation, an early marker of apoptosis. The authors concluded that TNF-alpha resulted in sphingomyelin hydrolysis, production of ceramide, and ceramide-mediated apoptosis.
Franchimont et al. (1999) examined the ability of TNFA and IL10 (124092) to regulate differentially the sensitivity of human monocytes/macrophages to glucocorticoids. Dexamethasone had different effects on LPS-induced TNFA and IL10 secretion; whereas it suppressed TNFA in a dose-dependent fashion, its effect on IL10 secretion was biphasic, producing stimulation at lower doses and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL10 secretion (P less than 0.001). Pretreatment with TNFA diminished, and with IL10 improved, the ability of dexamethasone to suppress IL6 (147620) secretion in whole-blood cell cultures (P less than 0.01 for both) and to enhance IL1 receptor antagonist (IL1RN; 147679) secretion by U937 cells (P less than 0.05 for both). TNFA decreased (P less than 0.001), while IL10 increased (P less than 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. The authors concluded that glucocorticoids differentially modulate TNFA and IL10 secretion by human monocytes in an LPS dose-dependent fashion, and that the sensitivity of these cells to glucocorticoids is altered by TNFA or IL10 pretreatment; TNFA blocks their effects, whereas IL10 acts synergistically with glucocorticoids.
Garcia-Ruiz et al. (2003) studied the contribution of ASM in TNF-alpha-mediated hepatocellular apoptosis. They showed that selective mGSH (mitochondrial glutathione) depletion sensitized hepatocytes to TNF-alpha-mediated hepatocellular apoptosis by facilitating the onset of mitochondrial permeability transition. Inactivation of endogenous hepatocellular ASM activity protected hepatocytes from TNF-alpha-induced cell death. Similarly, ASM -/- mice were resistant in vivo to endogenous and exogenous TNF-alpha-induced liver damage. Targeting of ganglioside GD3 (601123) to mitochondria occurred in ASM +/+ but not in ASM -/- hepatocytes. Treatment of ASM -/- hepatocytes with exogenous ASM induced the colocalization of GD3 and mitochondria. Garcia-Ruiz et al. (2003) concluded that ASM contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the targeting of mitochondria by glycosphingolipids.
Beattie et al. (2002) demonstrated that TNF-alpha, produced by glia, enhances synaptic efficacy by increasing surface expression of AMPA receptors. Preventing the actions of endogenous TNF-alpha has the opposite effects. Thus, Beattie et al. (2002) concluded that the continual presence of TNF-alpha is required for preservation of synaptic strength at excitatory synapses. Through its effects on AMPA receptor trafficking, TNF-alpha may play roles in synaptic plasticity and modulating responses to neural injury.
Ruuls and Sedgwick (1999) reviewed the problem of unlinking TNF biology from that of the MHC. Dysregulation and, in particular, overproduction of TNF have been implicated in a variety of human diseases, including sepsis, cerebral malaria (611162), and autoimmune diseases such as multiple sclerosis (MS; 126200), rheumatoid arthritis, systemic lupus erythematosus (152700), and Crohn disease (see 266600), as well as cancer. Susceptibility to many of these diseases is thought to have a genetic basis, and the TNF gene is considered a candidate predisposing gene. However, unraveling the importance of genetic variation in the TNF gene to disease susceptibility or severity is complicated by its location within the MHC, a highly polymorphic region that encodes numerous genes involved in immunologic responses. Ruuls and Sedgwick (1999) reviewed studies that had analyzed the contribution of TNF and related genes to susceptibility to human disease, and they discussed how the presence of the TNF gene within the MHC may potentially complicate the interpretation of studies in animal models in which the TNF gene is experimentally manipulated.
Janssen et al. (2002) studied macrophage and T-cell function in 8 patients from 3 unrelated families with partial IFNGR1 deficiency (IMD27B; 615978). They found that, in response to IFNG (147570) stimulation, TNF production was normal, but IL12 (see 161560) production and CD64 (FCGR1A; 146760) upregulation were strongly reduced, and macrophage killing of Salmonella typhimurium or Toxoplasma gondii was completely abrogated. Clinically, the patients suffered from infections with nontuberculous mycobacteria and Salmonella, but not T. gondii, even though 6 of 8 patients had serologic evidence of exposure to T. gondii. Further studies in control and patient macrophages revealed that IFNG-induced killing of T. gondii was partially mediated by TNF, whereas IFNG-induced killing of S. typhimurium appeared to be independent of TNF. Janssen et al. (2002) proposed that the divergent role of TNF in IFNG-induced killing of the intracellular pathogens T. gondii, S. typhimurium, and nontuberculous mycobacteria may explain the selective susceptibility of patients with partial IFNGR1 deficiency to these organisms.
Progressive oligodendrocyte loss is part of the pathogenesis of MS. Oligodendrocytes are vulnerable to a variety of mediators of cell death, including free radicals, proteases, inflammatory cytokines, and glutamate excitotoxicity. Proinflammatory cytokine release in MS is mediated in part by microglial activation. Takahashi et al. (2003) found that interleukin-1-beta (IL1B; 147720) and TNF-alpha, prominent microglia-derived cytokines, caused oligodendrocyte death in coculture with astrocytes and microglia, but not in pure culture of oligodendrocytes alone. Because IL1B had been shown to impair the activity of astrocytes in the uptake and metabolism of glutamate, Takahashi et al. (2003) hypothesized that the indirect toxic effect of microglia-derived IL1B and TNFA on oligodendrocytes involved increased glutamate excitotoxicity via modulation of astrocyte activity. In support, antagonists at glutamate receptors blocked the toxicity. The findings provided a mechanistic link between microglial activation in MS with glutamate-induced oligodendrocyte destruction.
Steed et al. (2003) used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs were thought to represent a possible approach to antiinflammatory biotherapeutics, and experiments in animal models showed that the strategy can attenuate TNF-mediated pathology.
Using an integrated approach comprising tandem affinity purification, liquid chromatography tandem mass spectrometry, network analysis, and directed functional perturbation studies using RNA interference or loss-of-function analysis, Bouwmeester et al. (2004) identified 221 molecular associations and 80 previously unknown interactors, including 10 novel functional modulators, of the TNFA/NFKB signal transduction pathway.
Kamata et al. (2005) found that TNF-alpha-induced reactive oxygen species (ROS), whose accumulation could be suppressed by mitochondrial superoxide dismutase (SOD2; 147460), caused oxidation and inhibition of JNK (see 601158)-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This resulted in sustained JNK activation, which is required for cytochrome c (see 123995) release and caspase-3 (CASP3; 600636) cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevented H2O2 accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevented TNF-alpha-mediated fulminant liver failure without affecting liver regeneration.
Membrane traffic in activated macrophages is required for 2 critical events in innate immunity: proinflammatory cytokine secretion and phagocytosis of pathogens. Murray et al. (2005) found a joint trafficking pathway linking both actions, which may economize membrane transport and augment the immune response. TNFA is trafficked from the Golgi to the recycling endosome, where vesicle-associated membrane protein-3 (VAMP3; 603657) mediates its delivery to the cell surface at the site of phagocytic cup formation. Fusion of the recycling endosome at the cup simultaneously allows rapid release of TNF-alpha and expands the membrane for phagocytosis.
Using live-cell imaging, Lieu et al. (2008) showed that tubules and carriers expressing p230 (GOLGA4; 602509) selectively mediated TNF transport from the trans-Golgi network (TGN) in HeLa cells. LPS activation of macrophages caused a dramatic increase in p230-labeled tubules and carriers emerging from the TGN. Depletion of p230 in macrophages reduced cell surface delivery of TNF more than 10-fold compared with control cells. Mice with RNA interference-mediated silencing of p230 also had dramatically reduced surface expression of Tnf. Lieu et al. (2008) concluded that p230 is a key regulator of TNF secretion and that LPS activation of macrophages increases Golgi carriers for export.
Stellwagen and Malenka (2006) showed that synaptic scaling in response to prolonged blockade of activity is mediated by the proinflammatory cytokine TNF-alpha. Using mixtures of wildtype and TNF-alpha-deficient neurons and glia, they showed that glia are the source of the TNF-alpha that is required for this form of synaptic scaling. Stellwagen and Malenka (2006) suggested that by modulating TNF-alpha levels, glia actively participate in the homeostatic activity-dependent regulation of synaptic connectivity.
Kawane et al. (2006) showed that DNase II (see 126350)-null/interferon type I receptor (IFNIR)-null mice and mice with an induced deletion of the DNase II gene developed a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anticyclic citrullinated peptide antibody, rheumatoid factor, and matrix metalloproteinase-3 (see 185250). Early in the pathogenesis, expression of the TNFA gene was upregulated in the bone marrow, and administration of anti-TNFA antibody prevented the development of arthritis. Kawane et al. (2006) concluded that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNFA, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.
Tay et al. (2010) used high-throughput microfluidic cell culture and fluorescence microscopy, quantitative gene expression analysis, and mathematical modeling to investigate how single mammalian cells respond to different concentrations of TNF-alpha and relay information to the gene expression programs by means of the transcription factor NF-kappa-B (see 164011). Tay et al. (2010) measured NF-kappa-B activity in thousands of live cells under TNF-alpha doses covering 4 orders of magnitude. They found that, in contrast to population-level studies with bulk assays, the activation was heterogeneous and was a digital process at the single-cell level with fewer cells responding at lower doses. Cells also encoded a subtle set of analog parameters, including NF-kappa-B peak intensity, response time, and number of oscillations, to modulate the outcome. Tay et al. (2010) developed a stochastic mathematical model that reproduced both the digital and analog dynamics, as well as most gene expression profiles, at all measured conditions, constituting a broadly applicable model for TNA-alpha-induced NF-kappa-B signaling in various types of cells.
Francisella tularensis, the causative agent of tularemia and a potential biohazard threat, evades the immune response, including innate responses through the lipopolysaccharide receptor TLR4 (603030), thus increasing its virulence. Huang et al. (2010) deleted the bacterium's ripA gene and found that mouse macrophages and a human monocyte line produced significant amounts of the inflammatory cytokines TNF, IL18 (600953), and IL1B in response to the mutant. IL1B and IL18 secretion was dependent on PYCARD (606838) and CASP1 (147678), and MYD88 (602170) was required for inflammatory cytokine synthesis. A complemented strain with restored expression of ripA restored immune evasion, as well as activation of the MAP kinases ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948), JNK, and p38 (MAPK14; 600289). Pharmacologic inhibition of these MAPKs reduced cytokine induction by the ripA deletion mutant. Mice infected with the mutant exhibited stronger Il1b and Tnfa responses than mice infected with the wildtype live vaccine strain. Huang et al. (2010) concluded that the F. tularensis ripA gene product functions by suppressing MAPK pathways and circumventing the inflammasome response.
Gunther et al. (2011) demonstrated a critical role for caspase-8 (CASP8; 601763) in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8-delta-IEC) spontaneously developed inflammatory lesions in the terminal ileum were highly susceptible to colitis. These mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8-delta-IEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by TNF-alpha, was associated with increased expression of receptor-interacting protein-3 (RIP3; 605817), and could be inhibited on blockade of necroptosis. Lastly, Gunther et al. (2011) identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Gunther et al. (2011) concluded that their data demonstrated a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-alpha-induced necroptotic cell death.
Braumuller et al. (2013) showed that the combined action of the T helper-1-cell cytokines IFN-gamma and TNF directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumor immunity from oncogene-induced senescence, Braumuller et al. (2013) used a mouse model in which the Simian virus-40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumors by attenuating p53 (191170)- and Rb (614041)-mediated cell cycle control. When combined, Ifng and Tnf drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16Ink4a (CDKN2A; 600160), and downstream Rb hypophosphorylation at ser795. This cytokine-induced senescence strictly requires Stat1 (600555) and Tnfr1 (TNFRSF1A; 191190) signaling in addition to p16Ink4a. In vivo, Tag-specific T-helper-1 cells permanently arrest Tag-expressing cancers by inducing Ifng- and Tnfr1-dependent senescence. Conversely, Tnfr1-null Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in Tnfr1-expressing hosts. Braumuller et al. (2013) concluded that as IFNG and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
Li et al. (2014) found that knockdown of the long noncoding RNA THRIL (615622) in human THP1 macrophages strongly suppressed TNF induction. Expression of TNF resulted in decreased expression of THRIL. Pull-down analysis identified a specific interaction of THRIL, primarily its 5-prime end, with HNRNPL (603083). Knockdown of HNRNPL resulted in decreased TNF production by stimulated THP1 cells. Chromatin immunoprecipitation analysis revealed binding of HNRNPL to the TNF promoter, and chromatin isolation by RNA purification assays showed that THRIL was also present at the TNF promoter. Knockdown of THRIL reduced binding of HNRNPL to the TNF promoter. Li et al. (2014) concluded that HNRNPL and THRIL form a ribonucleoprotein complex that stimulates TNF transcription by binding to its promoter. By examining RNA samples from patients with Kawasaki disease (611775), Li et al. (2014) observed that THRIL expression was significantly lower in the acute phase, when serum TNF levels are elevated, compared with the convalescent phase. They proposed that the low levels of THRIL when TNF levels are high in Kawasaki disease mirrors the negative-feedback loop of THRIL regulation observed in in vitro experiments and suggested that THRIL may be a biomarker for immune activation.
Role in Psoriasis
Inflammatory cytokines such as TNF have been implicated in the pathogenesis of psoriasis (see 177900) (Bonifati and Ameglio, 1999). Leonardi et al. (2003) found that treatment with the TNF antagonist etanercept led to a significant reduction in the severity of psoriasis over a treatment period of 24 weeks.
Boyman et al. (2004) engrafted keratome biopsies of human symptomless prepsoriatic skin onto AGR129 mice, which are deficient in type I and type II interferon receptors (see 107450 and 107470, respectively), as well as Rag2 (179616), and thereby lack B and T cells and show severely impaired NK cell activity. Upon engraftment, human T cells underwent local proliferation, which was crucial for development of a psoriatic phenotype exhibiting papillomatosis and acanthosis. Immunohistochemical analysis of prepsoriatic skin before transplantation and 8 weeks after transplantation showed activation of epidermal keratinocytes, dendritic cells, endothelial cells, and immune cells in the transplanted tissue. T-cell proliferation and the subsequent disease development were dependent on TNF production and could be inhibited by antibody or soluble receptor to TNF. Boyman et al. (2004) concluded that TNF-dependent activation of resident T cells is necessary and sufficient for development of psoriatic lesions.
Role in Rheumatoid Arthritis and Ankylosing Spondylitis
TNF-alpha may play a part in the pathogenesis of ankylosing spondylitis (106300) and rheumatoid arthritis (RA; 180300). Gorman et al. (2002) tested the efficacy of inhibition of TNF-alpha in treatment of ankylosing spondylitis. They used etanercept, a dimeric fusion protein of the human 75-kD (p75) TNFR2 (TNFRSF1B; 191191) linked to the Fc portion of human IgG1 (147100). Treatment in 40 patients with active, inflammatory disease for 4 months resulted in rapid, significant, and sustained improvement.
Nadkarni et al. (2007) had previously shown that anti-TNF (infliximab) therapy could overcome the inability of CD4 (186940)-positive/CD25 (IL2RA; 147730)-high regulatory T (Treg) cells from RA patients to suppress proinflammatory cytokine production by CD4-positive/CD25-negative T cells. Using flow cytometric analysis, they demonstrated that infliximab therapy induced a CD4-positive/CD25-high/FOXP3 (300292)-positive Treg population that mediated suppression via TGFB and IL10 and lacked expression of CD62L (SELL; 153240), a marker for CD4-positive/CD25-high/FOXP3-positive 'natural' Tregs. Natural Tregs remained defective in RA patients even after infliximab treatment. Nadkarni et al. (2007) concluded that anti-TNF therapy in RA patients induces a newly differentiated population of Tregs capable of restoring tolerance and compensating for defective natural Tregs.
Role in Tuberculosis
Studies in mice (Flynn et al., 1995) and observations in patients receiving infliximab (remicade) for treatment of rheumatoid arthritis (180300) or Crohn disease (see IBD3; 604519) (Keane et al., 2001) have shown that antibody-mediated neutralization of TNF increases susceptibility to tuberculosis (TB; 607948). However, excess TNF may be associated with severe TB pathology (Barnes et al., 1990). Using path and segregation analysis and controlling for environmental differences, Stein et al. (2005) evaluated TNF secretion levels in Ugandan TB patients. The results suggested that there is a strong genetic influence, due to a major gene, on TNF expression in TB, and that there may be heterozygote advantage. The effect of shared environment on TNF expression in TB was minimal. Stein et al. (2005) concluded that TNF is an endophenotype for TB that may increase power to detect disease-predisposing loci.
Role in Autosomal Dominant Polycystic Kidney Disease
Li et al. (2008) showed that TNF-alpha, which is found in cystic fluid of humans with autosomal dominant polycystic kidney disease (ADPKD; see 173900), disrupted the localization of polycystin-2 (PKD2; 173910) to the plasma membrane and primary cilia through TNF-alpha-induced scaffold protein FIP2 (OPTN; 602432). Treatment of mouse embryonic kidney organ cultures with TNF-alpha resulted in cyst formation, and this effect was exacerbated in Pkd2 +/- kidneys. TNF-alpha also stimulated cyst formation in vivo in Pkd2 +/- mice, and treatment of Pkd2 +/- mice with a TNF-alpha inhibitor prevented cyst formation.
Single-nucleotide polymorphisms (SNPs) in regulatory regions of cytokine genes have been associated with susceptibility to a number of complex disorders. TNF is a proinflammatory cytokine that provides a rapid form of host defense against infection but is fatal in excess. Because TNF is employed against a variety of pathogens, each involving a different pattern of risks and benefits, it might be expected that this would favor diversity in the genetic elements that control TNF production.
Herrmann et al. (1998) used PCR-SSCP and sequencing to screen the entire coding region and 1,053 bp upstream of the transcription start site of the TNFA gene for polymorphisms. Five polymorphisms were identified: 4 were located in the upstream region at positions -857, -851, -308 (191160.0004), and -238 from the first transcribed nucleotide, and 1 was found in a nontranslated region at position +691.
Three SNPs located at nucleotides -238, -308, and -376 (191160.0003) with respect to the TNF transcriptional start site are all substitutions of adenine for guanine. Knight et al. (1999) referred to the allelic types as -238G/-238A, -308G/-308A, and -376G/-376A. They stated that variation in the TNFA promoter region had been found to be associated with susceptibility to cerebral malaria (McGuire et al., 1994), with mucocutaneous leishmaniasis (Cabrera et al., 1995), with death from meningococcal disease (Nadel et al., 1996), with lepromatous leprosy (Roy et al., 1997), with scarring trachoma (Conway et al., 1997), and with asthma (Moffatt and Cookson, 1997).
Flori et al. (2003) tested for linkage between polymorphisms within the MHC region and mild malaria; see 609148. Two-point analysis indicated linkage of mild malaria to TNFd (lod = 3.27), a highly polymorphic marker in the MHC region. Multipoint analysis also indicated evidence for linkage of mild malaria to the MHC region, with a peak close to TNF (lod = 3.86). The authors proposed that genetic variation within TNF may influence susceptibility to mild malaria, but the polymorphisms TNF-238, TNF-244, and TNF-308 (191160.0004) are unlikely to explain linkage of mild malaria to the MHC region.
Statistical analyses by Funayama et al. (2004) showed a possible interaction between polymorphisms in the optineurin (OPTN; 602432) and TNF genes that would increase the risk for the development and probably progression of glaucoma in Japanese patients with POAG (137760).
By sequencing the promoter regions 500 bp upstream from the transcriptional start sites of members of the TNF and TNFR superfamilies, Kim et al. (2005) identified 23 novel regulatory SNPs in Korean donors. Sequence analysis suggested that 9 of the SNPs altered putative transcription factor binding sites. Analysis of SNP databases suggested that the SNP allele frequencies were similar to those for Japanese subjects but distinct from those of Caucasian or African populations.
Insulin Resistance and Diabetes
Zinman et al. (1999) studied the relationship between TNF-alpha and anthropometric and physiologic variables associated with insulin resistance and diabetes in an isolated Native Canadian population with very high rates of NIDDM (125853). Using the homeostasis assessment (HOMA) model to estimate insulin resistance, they found moderate, but statistically significant, correlations between TNF-alpha and fasting insulin, HOMA insulin resistance, waist circumference, fasting triglycerides, and systolic blood pressure; in all cases, coefficients for females were stronger than those for males. The authors concluded that in this homogeneous Native Canadian population, circulating TNF-alpha concentrations were positively correlated with insulin resistance across a spectrum of glucose tolerance. The data suggested a possible role for TNF-alpha in the pathophysiology of insulin resistance.
Rasmussen et al. (2000) investigated whether the -308 and -238 G-to-A genetic variants of TNF were associated with features of the insulin resistance syndrome or alterations in birth weight in 2 Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome. Birth weight and the ponderal index were also not associated with the polymorphisms. Their study did not support a major role of the -308 or -238 substitutions in TNF in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects.
Obayashi et al. (2000) investigated the influence of TNF-alpha on the predisposition to insulin dependency in adult-onset diabetic patients with type I diabetes (IDDM; 222100)-protective HLA haplotypes. Also see HLA-DQB1 (604305). The TNF-alpha of 3 groups of DRB1*1502-DQB1*0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 year was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 years of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 years. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1*1502-DQB1*0601 was strongly associated with the TNFA-13 allele. DRB1*1502-DQB1*0601 was strongly associated with the TNFA-12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFA-12 and non-TNFA-13 in group B reacted with GAD65 protein by Western blot. The authors concluded that TNF-alpha is associated with a predisposition to progression to insulin dependency in GADab/DRB1*1502-DQB1*0601-positive diabetic patients initially diagnosed with type II diabetes and that determination of these patients' TNF-alpha genotype may allow for better prediction of their clinical course.
To study whether the TNFA gene could be a modifying gene for diabetes, Li et al. (2003) studied TNFA promoter polymorphisms (G-to-A substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 diabetes patients from families with both type 1 and type 2 diabetes (type 1/2 families) or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNFA(308) AA/AG genotype frequency was increased in adult-onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P less than 0.0001 vs type 1). The TNFA(308) A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P less than 0.001 vs Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P less than 0.05 vs controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist-to-hip ratio [0.92 (0.12) vs 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. The authors concluded that TNFA is unlikely to be the second gene on the short arm of chromosome 6 responsible for modifying the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes.
Shbaklo et al. (2003) evaluated TNFA promoter polymorphisms at positions -863 (191160.0006) and -1031 and their association with type 1 diabetes in a group of 210 diabetic patients in Lebanon. Their results showed that in that population, the C allele is predominant at position -863, whereas the A allele is rare (2%). At position -1031, however, the C and T allele distribution was similar in both the patient (17.8% vs 82.2%, respectively) and the control (21.4% vs 79.6%) groups. No association of TNFA genotype at position 1031 with type 1 diabetes was found as demonstrated by the family-based association test and the transmission disequilibrium test. However, when patient genotypes were compared, the recessive CC genotype was found in type 1 diabetic males but not in type 1 diabetic females.
Coronary Heart Disease
From studies of 641 patients with myocardial infarction and 710 control subjects, Herrmann et al. (1998) concluded that polymorphisms of the TNFA gene are unlikely to contribute to coronary heart disease risk in an important way, but that the -308 mutation should be investigated further in relation to obesity.
Obesity
Because TNF-alpha expression had been reported to be increased in adipose tissue of both rodent models of obesity and obese humans, TNFA was considered a candidate gene for obesity (see 601665). Norman et al. (1995) scored Pima Indians for genotypes at 3 polymorphic dinucleotide repeat loci near the TNFA gene. In a sib-pair linkage analysis, the percentage of body fat, as measured by hydrostatic weighing, was linked (304 sib pairs, P = 0.002) to the marker closest (10 kb) to TNFA. The same marker was associated (P = 0.01) by analysis of variants with body mass index (BMI). To search for DNA variants in TNFA possibly contributing to obesity, they performed SSCP analysis on the gene from 20 obese and 20 lean subjects. No association could be demonstrated between alleles at the single polymorphism located in the promoter region and percent of body fat.
Rosmond et al. (2001) examined the potential impact of the G-to-A substitution at position -308 of the TNFA gene promoter on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones including salivary cortisol in 284 unrelated Swedish men born in 1944. Genotyping revealed allele frequencies of 0.77 for allele G and 0.23 for allele A. Tests for differences in salivary cortisol levels between the TNFA genotypes revealed that, in homozygotes for the rare allele in comparison with the other genotypes, there were significantly higher cortisol levels in the morning, before as well as 30 and 60 minutes after stimulation by a standardized lunch. In addition, homozygotes for the rare allele had a tendency toward higher mean values of body mass index, waist-to-hip ratio, and abdominal sagittal diameter compared with the other genotype groups. The results also indicated a weak trend toward elevated insulin and glucose levels among men with the A/A genotype. Rosmond et al. (2001) suggested that the increase in cortisol secretion associated with this polymorphism might be the endocrine mechanism underlying the previously observed association between the NcoI TNFA polymorphism and obesity, as well as insulin resistance.
Hyperandrogenism
To evaluate the role of TNF-alpha in the pathogenesis of hyperandrogenism, Escobar-Morreale et al. (2001) evaluated the serum TNF-alpha levels, as well as several polymorphisms in the promoter region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index. Hyperandrogenic patients presented with mildly increased serum TNF-alpha levels as compared with controls. When subjects were classified by body weight, serum TNF-alpha was increased only in lean patients as compared with lean controls; this difference was not statistically significant when comparing obese patients with obese controls. The TNF-alpha gene polymorphisms studied were equally distributed in hyperandrogenic patients and controls. However, carriers of the -308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. The authors concluded that the TNF-alpha system might contribute to the pathogenesis of hyperandrogenism.
Septic Shock
De Groof et al. (2002) evaluated the GH (see 139250)/IGF1 (147440) axis and the levels of IGF-binding proteins (IGFBPs), IGFBP3 protease (146732), glucose, insulin (176730), and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 days after admission. The median age was 22 months. Nonsurvivors had extremely high GH levels that were significantly different compared with mean GH levels in survivors during a 6-hour GH profile. Significant differences were found between nonsurvivors and survivors for the levels of total IGF1, free IGF1, IGFBP1, IGFBP3 protease activity, IL6 (147620), and TNFA. The pediatric risk of mortality score correlated significantly with levels of IGFBP1, IGFBP3 protease activity, IL6, and TNFA and with levels of total IGF1 and free IGF1. Levels of GH and IGFBP1 were extremely elevated in nonsurvivors, whereas total and free IGF1 levels were markedly decreased and were accompanied by high levels of the cytokines IL6 and TNFA.
Mira et al. (1999) reported the results of a multicenter case-control study of the frequency of the -308G-A polymorphism, which they called the TNF2 allele, in patients with septic shock. Eighty-nine patients with septic shock and 87 healthy unrelated blood donors were studied. Mortality among patients with septic shock was 54%. The polymorphism frequencies of the controls and patients differed only at the TNF2 allele (39% vs 18% in the septic shock and control groups, respectively, P = 0.002). Among the septic shock patients, TNF2 polymorphism frequency was significantly greater among those who had died (52% vs 24% in the survival group, P = 0.008). Concentrations of TNF-alpha were higher with TNF2 (68%) than with TNF1 (52%), but their median values were not statistically different. Mira et al. (1999) estimated that patients with the TNF2 allele had a 3.7-fold risk of death.
Cerebral Malaria
Because fatal cerebral malaria is associated with high circulating levels of tumor necrosis factor-alpha, McGuire et al. (1994) undertook a large case-control study in Gambian children. The study showed that homozygotes for the TNF2 allele, a variant of the TNFA gene promoter region (Wilson et al., 1992), had a relative risk of 7 for death or severe neurologic sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighboring HLA alleles, McGuire et al. (1994) showed that this disease association was independent of HLA class I and class II variation. The data suggested that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biologic advantage.
Hill (1999) reviewed the genetic basis of susceptibility and resistance to malaria, and tabulated 10 genes that are known to affect susceptibility or resistance to Plasmodium falciparum and/or Plasmodium vivax. He noted that the association of an upregulatory variant of the TNF gene promoter (Wilson et al., 1997) with cerebral malaria (McGuire et al., 1994) had encouraged the assessment of agents that might reduce the activity of this cytokine (van Hensbroek et al., 1996).
Through systematic DNA fingerprinting of the TNF promoter region, Knight et al. (1999) identified a SNP that causes the helix-turn-helix transcription factor OCT1 (POU2F1; 164175) to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT1-binding genotype, found in approximately 5% of Africans, was associated with 4-fold increased susceptibility to cerebral malaria in large studies comparing cases and controls in West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles. See 191160.0003.
Alopecia Areata
Galbraith and Pandey (1995) studied 2 polymorphic systems of tumor necrosis factor-alpha in 50 patients with alopecia areata (104000). The first biallelic TNFA polymorphism was detected in humans by Wilson et al. (1992); this involved a single base change from G to A at position -308 in the promoter region of the gene (191160.0004). The less common allele, A at -308 (called T2), shows an increased frequency in patients with IDDM, but this depends on the concurrent increase in HLA-DR3 with which T2 is associated. A second TNFA polymorphism, described by D'Alfonso and Richiardi (1994), also involves a G-to-A transition at position -238 of the gene. In alopecia areata, Galbraith and Pandey (1995) found that the distribution of T1/T2 phenotypes differed between patients with the patchy form of the disease and patients with totalis/universalis disease. There was no significant difference in the distribution of the phenotypes for the second system. The results suggested genetic heterogeneity between the 2 forms of alopecia areata and suggested that the TNFA gene is a closely linked locus within the major histocompatibility complex on chromosome 6 where this gene maps and may play a role in the pathogenesis of the patchy form of the disease.
Rheumatoid Arthritis
Mulcahy et al. (1996) determined the inheritance of 5 microsatellite markers from the TNF region in 50 multiplex rheumatoid arthritis (RA; 180300) families. Overall, 47 different haplotypes were observed. One of these was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P less than 0.005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% of the haplotypes not transmitted to affected offspring (P = 0.0003). Further study suggested that the tumor necrosis factor--lymphotoxin (TNF-LT) region influences susceptibility to RA, distinct from HLA-DR. The study illustrated the use of the transmission disequilibrium test (TDT) as described by Spielman et al. (1993).
Osteoporosis and Osteopenia
Ota et al. (2000) tested 192 sib pairs of adult Japanese women from 136 families for genetic linkage between osteoporosis and osteopenia phenotypes and allelic variants at the TNFA locus, using a dinucleotide repeat polymorphism located near the gene. The TNFA locus showed evidence for linkage to osteoporosis, with mean allele sharing of 0.478 (P = 0.30) in discordant pairs and 0.637 (P = 0.001) in concordant affected pairs. Linkage with osteopenia was also significant in concordant affected pairs (P = 0.017). Analyses limited to the postmenopausal women in their cohort showed similar or even stronger linkage for both phenotypes.
Asthma
Winchester et al. (2000) studied the association of the -308G-A variant of the TNFA gene and the insertion/deletion variant of angiotensin-converting enzyme (ACE; 106180) with a self-reported history of childhood asthma in 2 population groups. The -308A allele was significantly associated with self-reported childhood asthma in the UK/Irish population but not in the South Asian population. The ACE DD genotype was not associated with childhood asthma in either population. Thus, either the -308A allele or a linked major histocompatibility complex variant may be a genetic risk factor for childhood asthma in the UK/Irish sample.
Inflammatory Bowel Diseases
Koss et al. (2000) found that women but not men with extensive compared to distal colitis (see IBD3, 604519) were significantly more likely to bear the -308G-A promoter polymorphism of the TNF gene (191160.0004). The association was even stronger in women who also had an A rather than a C at position 720 in the LTA gene (153440). These polymorphisms were also associated with significantly higher TNF production in patients with Crohn disease, whereas an A instead of a G at position -238 in the TNF gene was associated with lower production of TNF in patients with ulcerative colitis.
For additional discussion of an association between variation in the TNF gene and inflammatory bowel disease, see IBD3 (604519).
Hepatitis B
To investigate whether TNF-alpha promoter polymorphisms are associated with clearance of hepatitis B virus (HBV) infection, Kim et al. (2003) genotyped 1,400 Korean subjects, 1,109 of whom were chronic HBV carriers and 291 who spontaneously recovered. The TNF promoter alleles that were previously reported to be associated with higher plasma levels (presence of -308A or the absence of -863A alleles), were strongly associated with the resolution of HBV infection. Haplotype analysis revealed that TNF-alpha haplotype 1 (-1031T; -863C; -857C; -308G; -238G; -163G) and haplotype 2 (-1031C; -863A; -857C; -308G; -238G; -163G) were significantly associated with HBV clearance, showing protective antibody production and persistent HBV infection, respectively (P = 0.003-0.02).
Cystic Fibrosis
Buranawuti et al. (2007) determined the TNF-alpha-238 and -308 genotypes in 3 groups of patients with cystic fibrosis (CF; 219700): 101 children under 17 years of age, 115 adults, and 38 nonsurviving adults (21 deceased and 17 lung transplant after 17 years of age). Genotype frequencies among adults and children with CF differed for TNF-alpha-238 (G/G vs G/A, p = 0.022), suggesting that TNF-alpha-238 G/A is associated with an increased chance of surviving beyond 17 years of age. When adults with CF were compared to nonsurviving adults with CF, genotype frequencies again differed (TNF-alpha 238 G/G vs G/A, p = 0.0015), and the hazard ratio for TNF-alpha-238 G/G versus G/A was 0.25. Buranawuti et al. (2007) concluded that the TNF-alpha-238 G/A genotype appears to be a genetic modifier of survival in patients with CF.
Role in HLA-B27-Associated Uveitis
In a study of 114 Caucasian patients with HLA-B27-associated uveitis compared with 63 healthy unrelated HLA-B27-positive blood donors and 88 healthy unrelated HLA-B27-negative individuals, El-Shabrawi et al. (2006) found that the frequencies of the TNF-alpha -308GA and -238GA genotypes were significantly lower in patients with HLA-B27-associated uveitis (6.1% and 0%, respectively) when compared with the HLA-B27-negative group, 23% at -308 (p = 0.003), and 7.9% at -238 (p = 0.0003). The frequency of the -238GA genotype was also significantly lower in patients than among the healthy HLA-B27-positive group. The authors concluded that HLA-B27-positive individuals show a higher susceptibility towards development of intraocular inflammation in the presence of an A allele at nucleotide -238, and to a lesser degree, at nucleotide -308 of the TNF-alpha gene promoter.
Nedwin et al. (1985) determined that TNFA and LTA genes have similar structures; each spans about 3 kb and contains 4 exons. Only the last exons of these genes, which code more than 80% of the secreted protein, are significantly homologous (56%).
By analysis of human-mouse somatic cell hybrids, Nedwin et al. (1985) found that TNFA and TNFB are closely linked on chromosome 6. Study of hybrid cells made with rearranged human chromosome 6 showed that both TNFA and TNFB map to the 6p23-q12 segment. Nedwin et al. (1985) speculated that close situation of these 2 loci to HLA 'may be useful for a coordinate regulation of immune system gene products.' By Southern blot analysis of a panel of major histocompatibility complex deletion mutants, Spies et al. (1986) established that TNFA and TNFB are closely linked and situated in the MHC either between HLA-DR (see 142860) and HLA-A (142800) or centromeric of HLA-DP (see 142858). By in situ hybridization, they assigned TNFA and TNFB to 6p21.3-p21.1. By pulsed field gel electrophoresis, Carroll et al. (1987) showed that the TNF genes are located 200 kb centromeric of HLA-B (142830) and about 350 kb telomeric of the class I cluster. The TNFA and TNFB genes are separated by 1 to 2 kb of DNA. By hybridization to fragments of NruI-digested DNA, Ragoussis et al. (1988) demonstrated that the TNFA/TNFB genes lie between C2 of class III and HLA-B of class I.
Nedospasov et al. (1986) showed that, in the mouse, TNFA and TNFB are likewise tandemly arranged and situated on chromosome 17, which bears much homology of synteny with chromosome 6 of man. Muller et al. (1987) mapped both tumor necrosis factor and lymphotoxin close to H-2D in the mouse major histocompatibility complex on chromosome 14. By pulsed field gel electrophoresis, Inoko and Trowsdale (1987) showed that the human TNFA and TNFB genes are linked to the HLA-B locus, analogous to their position in the mouse, where they are located between the class III region and H-2D. However, the distance between the TNF genes and the class I region was much greater in man, namely, about 260 kb, compared to 70 kb in the mouse.
As noted, the region spanning the tumor necrosis factor (TNF) cluster in the human major histocompatibility complex (MHC) has been implicated in susceptibility to numerous immunopathologic diseases, including type 1 diabetes mellitus (IDDM; 222100) and rheumatoid arthritis (180300). However, strong linkage disequilibrium across the MHC has hampered the identification of the precise genes involved. In addition, the observation of 'blocks' of DNA in the MHC within which recombination is very rare limits the resolution that may be obtained by genotyping individual SNPs. To gain a greater understanding of the haplotypes of the block spanning the TNF cluster, Allcock et al. (2004) genotyped 32 HLA-homozygous cell lines and 300 healthy control samples for 19 coding and promoter region SNPs spanning 45 kb in the central MHC near the TNF genes. The workshop cell lines defined 11 SNP haplotypes that account for approximately 80% of the haplotypes observed in the 300 control individuals. Using the control individuals, they defined a further 6 haplotypes that account for an additional 10% of donors. They showed that the 17 haplotypes of the 'TNF block' can be identified using 15 SNPs.
The TNF block studied by Allcock et al. (2004) includes the TNF genes (TNFA; LTA, 153440; and LTB, 600978), as well as AIF1 (601833), the activating NK receptor NCR3 (611550), NFKBIL1 (601022), ATP6P1G (606853), and BAT1 (142560).
Old (1985) recounted the series of observations, experiments and discoveries that led up to definition of human TNF and cloning of the gene. He referred to cloning as 'an important rite of passage for biological factors such as TNF, and there is a growing sense that a factor has to be cloned before it is taken very seriously.' He paraphrased Descartes: 'It's been cloned, therefore it exists.'
Feldmann and Maini (2010) reviewed the findings that led to targeting of TNF in the treatment of rheumatoid arthritis and other chronic diseases and offered an appreciation of the role of cytokines in medicine.
Bruce et al. (1996) used targeted gene disruption to generate mice lacking either the p55 (TNFRSF1A; 191190) or the p75 TNF receptors; mice lacking both p55 and p75 were generated from crosses of the singly deficient mice. The TNFR-deficient (TNFR-KO) mice exhibited no overt phenotype under unchallenged conditions. Bruce et al. (1996) reported that damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in the TNFR-KO mice, indicating that TNF serves a neuroprotective function. Their studies indicated that TNF protects neurons by stimulating antioxidative pathways. Injury-induced microglial activation was suppressed in TNFR-KO mice. They concluded that drugs which target TNF signaling pathways may prove beneficial in treating stroke or traumatic brain injury.
Marino et al. (1997) generated knockout mice deficient in TNF and characterized the response of these mice to a variety of inflammatory, infectious, and antigenic stimuli.
Uysal et al. (1997) generated obese mice with a targeted null mutation in the genes for Tnf and its p55 and p75 receptors. The absence of TNF resulted in significantly improved insulin sensitivity in both diet-induced obesity and the ob/ob (see 164160) model of obesity. Tnf-deficient mice had lower levels of circulating free fatty acids and were protected from the obesity-related reduction in insulin receptor signaling in muscle and fat tissues. Uysal et al. (1997) concluded that TNF is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.
Roach et al. (2002) noted that TNF is essential for the formation and maintenance of granulomas and for resistance against infection with Mycobacterium tuberculosis. Mice lacking Tnf mount a delayed chemokine response associated with a delayed cellular infiltrate. Subsequent excessive chemokine production and an intense but loose and undifferentiated cluster of T cells and macrophages, capable of producing high levels of Ifng in vitro, were unable to protect Tnf -/- mice from fatal tuberculosis after approximately 28 days, whereas all wildtype mice survived for at least 16 weeks. Roach et al. (2002) concluded that TNF is required for the early induction of chemokine production and the recruitment of cells forming a protective granuloma. The TNF-independent production of chemokines results in a dysregulated inflammatory response unable to contain M. tuberculosis, which suggests a mechanism for the reactivation of clinical tuberculosis observed by Keane et al. (2001) in patients undergoing treatment for rheumatoid arthritis (180300) or Crohn disease (see 266600) with a humanized monoclonal antibody to TNF.
Diwan et al. (2004) compared transgenic mice with targeted cardiac overexpression of secreted wildtype Tnf to transgenic mice with targeted cardiac overexpression of a noncleavable transmembrane form of Tnf. Both lines of mice had overlapping levels of myocardial Tnf protein, but developed strikingly different cardiac phenotypes: the mice overexpressing the transmembrane form of Tnf developed concentric left ventricular hypertrophy, whereas the mice overexpressing secreted Tnf had dilated left ventricular hypertrophy. Diwan et al. (2004) suggested that posttranslational processing of TNF by ADAM17 (603639), as opposed to TNF expression per se, is responsible for the adverse cardiac remodeling that occurs after sustained TNF overexpression.
Vielhauer et al. (2005) studied immune complex-mediated glomerulonephritis in Tnfr1- and Tnfr2-deficient mice. Proteinuria and renal pathology were initially milder in Tnfr1-deficient mice, but at later time points were similar to those in wildtype controls, with excessive renal T-cell accumulation and reduced T-cell apoptosis. In contrast, Tnfr2-deficient mice were completely protected from glomerulonephritis at all time points, despite an intact immune system response. Tnfr2 expression on intrinsic renal cells, but not leukocytes, was essential for glomerulonephritis and glomerular complement deposition. Vielhauer et al. (2005) concluded that the proinflammatory and immunosuppressive properties of TNF segregate at the level of its receptors, with TNFR1 promoting systemic immune responses and renal T-cell death and intrinsic renal cell TNFR2 playing a critical role in complement-dependent tissue injury.
In mice, Balosso et al. (2005) found that intrahippocampal injection of murine Tnfa or astrocytic overexpression of murine Tnfa inhibited the number and duration of kainate-induced seizures. Transgenic mice lacking p75 receptors showed increased seizure susceptibility, suggesting that the protective effect of Tnfa was mediated by p75 receptors. Immunohistochemical and Western blot analysis identified p75 receptors, but not p55 receptors, in the mouse hippocampus. The findings indicated a role for inflammatory pathways in the pathophysiology of seizures.
Both homozygous and heterozygous Tshr (603372)-null mice are osteopenic with evidence of enhanced osteoclast differentiation. Hase et al. (2006) found that increased osteoclastogenesis in these mice was rescued with graded reductions in the dosage of the Tnf gene.
Soller et al. (2007) reported that canine Tnf, Il1a (147760), and Il1b (147720) have high coding and protein sequence identity to human and other mammalian homologs. They suggested that dog models of cytokine-mediated human diseases may be highly informative.
Guo et al. (2008) noted that transgenic mice overexpressing human TNF exhibit reduced long bone volume, decreased mineralized bone nodule formation, and arthritis. They showed that TNF overexpression induced bone loss by increasing expression of Smurf1 (605568), resulting in ubiquitination and proteasomal degradation of Smad1 (601595) and Runx2 (600211). Deletion of Smurf1 in TNF-transgenic mice prevented systemic bone loss and improved bone strength.
Van Ostade et al. (1993) identified 2 cell lines with mutations in TNF that resulted in loss of almost all activity in the standard cytotoxic assay with the L929 murine fibrosarcoma cell line and were shown to have lost the binding affinity specifically for the TNF-R55 human receptor (191190). One of the mutants was found to carry a leu29-to-ser mutation and the other, an arg32-to-trp mutation (191160.0002). The remarkable ability of TNF, especially in combination with interferon, selectively to kill or inhibit malignant cell lines is unmatched by any other combination of cytokines. However, clinical trials have been disappointing, and it is estimated that a TNF dose would be effective only at 5 to 25 times the maximum tolerated dose. TNF binds to 2 types of receptors: the smaller, TNF-R55, is present on most cells and particularly on those susceptible to the cytotoxic action of TNF; the larger, TNF-R75 (191191), is also present on many cell types, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes. The selective binding of the mutant TNF to TNF-R55 might make it useful in cancer therapy.
See 191160.0001 and Van Ostade et al. (1993).
Knight et al. (1999) studied the significance of a single-nucleotide polymorphism (SNP) in the promoter region of TNF: a substitution of adenine for guanine at -376. Binding experiments showed that the transcription factor OCT1 (164175) can bind to site alpha of TNF, but that this binding is dependent on the presence of the TNF(-376A) allele. They showed, furthermore, that TNF(-376A) affects TNF expression in vitro. Since TNF has a pivotal role in human malaria, acting both to suppress parasitic growth and to cause clinical symptoms, Knight et al. (1999) investigated frequency of this allele in cases of cerebral malaria (611162) in the Gambia and in Kenya. They found an odds ratio (OR) of 4.3 for the -376A allele, compared with the control group. In both the Kenyan and the Gambian study populations, they found that the relatively rare -376A allele occurred only in individuals who also carried the more common -238A allele. The same had been reported in European populations. These results indicated that the -376 polymorphism occurred more recently in human evolution than the -238 polymorphism, and that it arose as a mutation of a haplotype bearing the -238A allele.
Mira et al. (1999) referred to the TNFA promoter polymorphisms at position -308 as TNF1 for guanine and TNF2 for adenine. In a multicenter study involving 7 institutions, they found a significant association between the TNF2 allele and susceptibility to septic shock and death from septic shock. The septic shock group was defined by the following 6 criteria within a 12-hour period: (1) clinical evidence of infection; (2) hyperthermia or hypothermia; (3) tachycardia; (4) tachypnea; (5) necessity for vasopressor to maintain systolic blood pressure; and (6) evidence of inadequate organ function or perfusion.
Moraes et al. (2001) found that the TNF2 polymorphism is significantly associated with a stronger response (Mitsuda reaction) to lepromin in borderline tuberculoid leprosy patients. Epigenetic factors such as a history of BCG vaccination or a reversal reaction, but not both, were also associated with boosted Mitsuda reactions. Moraes et al. (2001) concluded that augmented TNF production may be associated with the TNF2 allele and an increased granulomatous response.
Ma et al. (1998) found a higher frequency of the rare T2 TNFA polymorphism (-308G-A) in 43 Japanese Guillain-Barre syndrome (139393) patients who had had antecedent infection with C. jejuni than in 85 community controls.
Witte et al. (2002) evaluated the relation between the -308G-A promoter polymorphism and risk of asthma (600807) in 236 cases and 275 nonasthmatic controls. Logistic regression analyses indicated that having 1 or 2 copies of the -308A allele increased the risk of asthma (odds ratio = 1.58), the magnitude of which was increased when restricting the cases to those with acute asthma (odds ratio = 1.86, P = 0.04) or further restricting the subjects to those with a family history of asthma and those of European American ancestry (odds ratio = 3.16, P = 0.04).
Shin et al. (2004) genotyped 550 Korean asthmatics and 171 Korean controls at 5 SNPs in TNFA and 2 SNPs in TNFB. Six common haplotypes could be constructed in the TNF gene cluster. The -308G-A polymorphism showed a significant association with the risk of asthma (p = 0.0004). The frequency of the -308A allele-containing genotype in asthmatics (9.8%) was much lower than that in normal controls (22.9%). The protective effects of this polymorphism on asthma were also evident in separated subgroups by atopic status (p = 0.05 in nonatopic subjects and p = 0.003 in atopic subjects). The most common haplotype of the TNF gene cluster (TNF-ht1-GGTCCGG) was associated with total serum IgE levels (147050) in asthma patients, especially in nonatopic patients (p = 0.004). Shin et al. (2004) concluded that genetic variants of TNF may be involved in the development of asthma and total serum IgE level in bronchial asthma patients.
Aoki et al. (2006) did not find a significant association between the TNF -308G-A polymorphism and childhood atopic asthma in 2 independent Japanese populations; however, metaanalysis of a total of 2,477 asthma patients and 3,217 control individuals showed that the -308G-A polymorphism was significantly associated with asthma. The combined odds ratio was 1.46 for fixed or random effects (p = 0.0000001 and p = 0.00014, respectively).
Quasney et al. (2001) stated that immunologic mechanisms resulting in macrophage infiltration and glial cell activation in the brain are thought to be involved in the pathophysiology of HIV dementia. Moreover, elevated levels of TNF-alpha have been found in the brains of patients with HIV dementia. In a study of 16 patients with HIV dementia, 45 HIV-infected patients without dementia, and 231 controls, they found an increased frequency of the -308A allele in patients with HIV dementia (0.28 vs 0.11 in controls and 0.07 in HIV patients without dementia). There were no individuals with the A/A genotype in either of the HIV-infected groups. Quasney et al. (2001) noted that the -308A allele is associated with higher TNF-alpha secretion in response to an inflammatory stimulus and that evidence has shown a role for TNF-alpha in neuronal damage, thus suggesting a genetic predisposition to the development of HIV dementia.
Cox et al. (1994) reported that the -308A allele has an increased frequency in type I diabetes mellitus (222100). Krikovszky et al. (2002) studied ambulatory blood pressure in 126 Hungarian adolescents with type I diabetes mellitus. They found that the prevalence of the -308A allele was higher in diabetic adolescents than in the Hungarian reference population. TNFA genotype was associated with both systolic and diastolic blood pressure values. The -308A allele carrier state appeared to be associated with lower systolic and diastolic blood pressure values.
Szalai et al. (2002) found an increased frequency of the C4B*Q0 allele (see 120820) in patients with severe coronary artery disease (CAD) who underwent bypass surgery compared to healthy controls (14.2% vs 9.9%). Investigation of specific allelic combinations revealed that C4B*Q0 in combination with the TNF-alpha -308A allele was significantly higher in CAD patients, particularly those with preoperative myocardial infarction.
In a study of 147 patients with psoriatic arthritis (607507) and 389 controls, Balding et al. (2003) found that the -308A allele was significantly associated with both the presence and progression of joint erosions in psoriatic arthritis, and that the AA genotype was associated with the lowest mean age at onset of psoriasis (p = 0.0081).
In a group of 261 patients with migraine without aura (see, e.g., 157300), Rainero et al. (2004) found that the G/G genotype was associated with an increased risk of migraine (odds ratio of 3.30). Rainero et al. (2004) suggested that TNF-alpha may be involved in the pathogenesis of migraine, perhaps due to its effect on cerebral blood flow; alternatively, a closely linked locus may be involved.
In a metaanalysis of 19 studies, Lee et al. (2006) found an association between the -308A/A genotype and the -308A allele and systemic lupus erythematosus (SLE; 152700) in European-derived population (odds ratio of 4.0 for A/A and 2.1 for the A allele), but not in Asian-derived populations.
McCusker et al. (2001) typed the -850C-T polymorphism (rs1799724) in 242 patients with sporadic Alzheimer disease (104300), 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. The distribution of TNF-alpha genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2.51 (95% CI, 1.49-4.21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that possession of the T allele significantly increased the risk of Alzheimer disease associated with the APOE4 (see 107741) allele (odds ratio of 2.73 (1.68-4.44) for those with APOE4 and without TNF T, vs 4.62 (2.38-8.96) for those with APOE4 and TNF T).
Among 506 AD patients, Laws et al. (2005) found that presence of the -850 T allele conferred an odds ratio of 1.63 for disease development. Presence of the APOE4 allele and the T allele increased the odds ratio to 6.65, suggesting a synergistic effect. In addition, presence of the -850 T allele was associated with lower levels of CSF beta-amyloid-42 in patients with AD.
Skoog et al. (1999) studied the -863C-A promoter polymorphism of the TNF gene and found that the rare A allele associated with 31% lower transcriptional activity in human hepatoblastoma cells. Among 254 Swedish men, allele frequencies were 0.83 and 0.17 for the C and A alleles, respectively. Carriers of the A allele had significantly decreased serum TNF-alpha concentrations compared to carriers of the C allele. Electromobility shift assays showed that the -863A allele was associated with decreased binding of monocytic and hepatic nuclear factors to the promoter region of the TNF gene.
In a study of 265 patients with late-onset Alzheimer disease (AD; 104300) and 347 controls, Ramos et al. (2006) found an association between the -863A allele and decreased risk for disease development. The -863A allele was present in 16.9% of controls and 12.6% of patients. Comparison of the 3 genotypes (C/C, C/A, and A/A) suggested a dose-response effect with the A/A genotype conferring an odds ratio of 0.58. The findings supported a role for inflammation in AD.
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