Disease relevance of LTA

• Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, chi(2) = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls) [1].
• Selected TNF/LTA haplotypes were associated with spontaneous preterm birth in both African-American and white subjects [2].
• CONCLUSION: The nine polymorphisms studied in the TNF-LTA region did not show evidence for association or linkage with familial preeclampsia [3].
• The pro-inflammatory cytokine LTA (lymphotoxin-alpha) has multiple functions in regulating the immune system and may contribute to inflammatory processes leading to CHD (coronary heart disease) [4].
• The gene for LT beta was found next to the TNF-LT locus in the major histocompatibility complex (MHC), a region of the MHC with possible linkage to autoimmune disease [5].

Psychiatry related information on LTA

• Our results, which show for the first time strikingly increased CSF levels of TNF-alpha but not of TNF-beta, IL-1beta or IL-6 in AD and VAD, may form a conceptual framework for further studies of neuroprotective mechanisms in dementias [6].
• We assessed the correlation between cognitive functioning and the LTA Cys13Arg polymorphism in 351 individuals with schizophrenia, 122 with bipolar disorder, and 160 controls [7].
• In older women, Minnesota LTA (386 +/- 228 kcal/day) and Caltrac (379 +/- 162 kcal/day) underestimated physical activity by approximately 55% compared with DLW (873 +/- 244 kcal/day) [8].
• This study applies Latent Transition Analysis (LTA; Collins & Wugalter, 1992; Collins, Wugalter, & Rousculp, 1991) to movement through the stages of change for smoking cessation [9].

High impact information on LTA

• Disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens [10].
• LT is induced in an antigen-specific MHC restricted fashion from class I and class II restricted T cells [11].
• Viral infection is also associated with LT production by lymphoid cells [11].
• These findings provide a molecular model of how LTA expression may be genetically regulated by allele-specific recruitment of the transcriptional repressor ABF-1 [12].
• By detailed haplotypic analysis of the locus, we identified a single-nucleotide polymorphism (SNP) at LTA+80 as a main predictor of LTA protein production by human B cells [12].

Chemical compound and disease context of LTA

• Polymorphisms at position -308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis [13].
• Association of TNF-alpha and TNF-beta gene polymorphism with steroid receptor expression in breast cancer patients [14].
• In human T and B lymphocytes, the main producers of TNF-beta, in three instances of chronic lymphatic leukemias and two cases of non-Hodgkin lymphomas, all 5'-CG-3' sequences are unmethylated in this region [15].
• The effect of TNF-beta to stimulate adenylate cyclase appears to occur independent of pertussis toxin-sensitive substrate and may involve activation of phospholipase A [16].
• TNF-beta potentiation of adenylate cyclase activity and stimulation of 3H release from 3H arachidonic acid labeled cells was not prevented by pertussis toxin [16].

Biological context of LTA

• In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery [1].
• RESULTS: Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04 [17].
• To determine whether polymorphisms in the 5' flanking region of the TNFA gene (-1031C/T, -863C/A, and -857C/T) and an NcoI polymorphism in the TNFB gene (LTA NcoI) are associated with the development of asthma, we performed transmission disequilibrium tests of families identified through children with atopic asthma [18].
• Here three examples of microsatellites in the human major histocompatibility complex (HLA) are investigated, a (GT)n microsatellite situated 2 kb 5' off the lymphotoxin alpha (LTA) gene, a (GAA)n block in the 5' part of the HLA-F gene and a composite (GT)n(GA)m stretch in the second intron of HLA-DRBl genes [19].
• Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan [20].

Anatomical context of LTA

• Tumour necrosis factors, TNF-alpha and TNF-beta (previously called lymphotoxin), are the products of activated monocytes and lymphocytes, respectively, and both have recently been purified, sequenced and cloned by recombinant DNA methods, revealing 35% identity and 50% homology in the amino-acid sequence [21].
• Enriched lymphocyte preparations incubated with the staphylococcal toxin produced significant levels of TNF-like activity that is not neutralized by anti-rHuTNF antibodies and is likely to be lymphotoxin (LT or TNF-beta) [22].
• The highest amounts of TNFBP were seen in the sera of patients with B cell malignancies including hairy cell leukemia (HCL) and type B chronic lymphocytic leukemia [23].
• Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell [24].
• These studies suggest that activated T cells through the secretion of LT can in turn activate the local endothelial lining so as to promote homing and extravasation of inflammatory cells [25].

Associations of LTA with chemical compounds

• The lymphokine tumor necrosis factor (TNF) has a well-defined role as an inducer of inflammatory responses; however, the function of the structurally related molecule lymphotoxin (LT alpha) is unknown [5].
• Low concentrations of TNF-alpha were produced in response to both IL-12 and IL-7, with little or no TNF-beta production [26].
• We have investigated the correlation between different tumor necrosis factor (TNF) and class II major histocompatibility complex alleles in the lipopolysaccharide- or phytohemagglutinin-induced secretion of TNF-alpha and TNF-beta by human monocytes and peripheral blood mononuclear cells in 87 unrelated Danish male individuals [27].
• No association was found with acetylcholine-receptor levels or disease severity for any of the TNFA or TNFB polymorphisms [28].
• Concentrations of triglyceride rose significantly with increasing tertile only in subjects with a LT-alpha AA genotype [29].
• Homozygosity for the LTA +80A allele correlated with the lowest levels of plasmatic tumor-necrosis factor-alpha [30].

Physical interactions of LTA

• Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus [27].
• LT beta is a transmembrane protein that provides the membrane anchor for the attachment to the cell surface of the heteromeric complex of LT alpha and LT beta [31].
• While etanercept is a 75kD TNF receptor fusion protein that binds to TNFalpha and TNFbeta, infliximab is a chimeric monoclonal antibody that binds to TNFalpha both in its soluble form in the serum and on the cell membrane [32].
• Here we show that LTA protein binds to galectin-2, a member of the galactose-binding lectin family [33].
• Subsequently, a recombinant LT beta R was shown to bind LT alpha LT beta heteromeric complexes [34].

Enzymatic interactions of LTA

• Examination of enzyme-treated recombinant cytokines by gel electrophoresis revealed that cathepsin-G cleaved LT into a 12.6-kDa fragment and leukocyte elastase fragmented LT into a 14.1-kDa product [35].

Regulatory relationships of LTA

• IL-1 beta transcripts were expressed in fibroblastic and atypical cultures and TNF beta transcripts were expressed in syncytial and transitional cultures only [36].
• LT enhances the proliferation of activated B cells and augments B cell proliferation induced by IL-2 [37].
• These findings demonstrate that cell-surface LT-alpha is expressed in association with LT-beta on activated normal B cells and neoplastic B cells representing an activated state [38].
• In addition TNF-beta was induced in 3/10 and IFN-gamma in 5/10 non-responders [39].
• It appears TGF-beta 1 can down-regulate LT mRNA syntheses, mLT expression, and sLT secretion of human T-LAK cells in vitro [40].

Other interactions of LTA

• Furthermore, these LT actions can be augmented or complemented by other locally produced mediators such as IFN-gamma or IL 1 [25].
• By using a battery of anti-LT-alpha and LT-beta mAbs, it is clear that two LT surface forms exist on the surface of PMA-activated II-23 cells, a human T cell hybridoma [41].
• Some mRNA for IL-1 beta, TNF-beta, and interferon (IFN)-gamma was detected in only a few biopsies [42].
• In addition, the results suggest some overlap between the TNFR1 binding sites for TNF alpha and TNF beta, despite low amino acid sequence homology between these cytokines [43].
• Lymphotoxin (TNF-beta) was also shown to stimulate human thymocyte proliferation, demonstrating that TNF-beta can initiate a biologic response that is mediated by TNF-R2 [44].

Analytical, diagnostic and therapeutic context of LTA

• To determine the molecular basis of this disparity between LT and TNF the receptor binding characteristics of rTNF and rLT were investigated by direct and competitive radioligand assays on the II-23.D7 T hybridoma, and for comparison, anti-CD3 activated human T lymphocytes [45].
• Adding IVIg 24 h after SPE-A stimulation also resulted in reduced blast transformation and decreased synthesis of IFN-gamma and TNF-beta [46].
• Immunoprecipitation experiments with anti-LT monoclonal antibody (MAb) 9B9 from cell-surface radioiodinated JOK-I cells revealed that a cell-surface lymphotoxin molecule (25 kDa) is expressed in association with a 33-kDa molecule [38].
• Tumor necrosis factor alpha (TNFa) and lymphotoxin (LT) or TNF beta are closely linked cytokines produced by macrophages and activated T lymphocytes, which play important regulatory roles in the immune response to allografts [47].
• A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNF alpha, LT alpha and IL-10 genes [48].

References