Disease relevance of TNFRSF25

• Previously, DR3 has been shown to have a role in atherogenesis through stimulation of matrix degrading enzymes including matrix metalloproteinase (MMP)-9 [1].
• CrmA, a poxvirus inhibitor of Ced-3-like proteases which blocks death signaling by TNFR1 and CD95, inhibited Apo-3-induced apoptosis [2].
• Duplication of the DR3 gene on human chromosome 1p36 and its deletion in human neuroblastoma [3].
• A higher fraction of cells also express the TL1A receptor DR3 in ulcerative colitis and Crohn's disease [4].
• Two isoforms encoding the full-length transmembrane death receptor 3 (DR3) were isolated from mRNAs of a panel of human cell lines and tumor tissues obtained from patients with follicular non-Hodgkin's lymphoma [5].

Psychiatry related information on TNFRSF25

• HLA DR3 was associated with the familial dementia of the Alzheimer type patients [6].
• The results suggest that WSLP may be useful for gene therapy of erectile dysfunction [7].
• Although past alcohol consumption tended to be less in DR-3 positive patients in comparison with the other patients, the difference was not significant [8].

High impact information on TNFRSF25

• We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5, P=2.7x10(-4); single point MLS=4.5, P=2.7x10(-5)) [9].
• An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8, SC01, DR3] [10].
• WSL-1 also interacts specifically with the TNFR1-associated molecule TRADD [11].
• The structure shows that the CLIP fragment binds to DR3 in a way almost identical to that in which antigenic peptides bind class II histocompatibility glycoproteins [12].
• We have studied the molecular basis of HLA-DR polymorphism within such a group which includes the haplotypes DR3, DR5 and DRw6 [13].

Chemical compound and disease context of TNFRSF25

• Nine of 11 patients with C4A deletion had an HLA haplotype consistent with the MHC supratype HLA-A1, Cw7, B8, C4AQ0, C4B1, BfS, DR3 previously found to be associated with IgA deficiency [14].
• DRB genotyping supports recessive inheritance of DR3-associated susceptibility to insulin-dependent diabetes mellitus [15].
• We synthesized WSLP using branched polyethylenimine (PEI) of 1800 Da and cholesteryl chloroformate, and constructed p2CMVmIL-12, encoding the IL-12 subunits p35 and p40, each under the transcriptional control of a separate cytomegalovirus (CMV) promoter [16].
• Previous studies of sporadic inclusion body myositis (sIBM) have shown a strong association with HLA-DR3 and other components of the 8.1 ancestral haplotype (AH) (HLA-A1, B8, DR3), where the susceptibility locus has been mapped to the central major histocompatibility complex (MHC) region between HLA-DR and C4 [17].
• There was a significant association between proteinuria induced by D-penicillamine and the antigens DR3 and B8 [18].

Biological context of TNFRSF25

• These data confirm that TNF receptor family members are expressed in a regulated manner during renal transplant rejection, and identify DR3 as a potential inducible mediator of tubular inflammation and injury [19].
• Thus, DR3 likely plays a role in regulating lymphocyte homeostasis [20].
• Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95 [20].
• TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells [21].
• Our results also indicate that some methylation markers, such as those in regions of RASSF1A and TNFRSF25, might be of limited use for detection because they are also methylated in normal bladder tissues [22].

Anatomical context of TNFRSF25

• In ischemic allografts, eg, with acute tubular necrosis but no cellular rejection, DR3 was induced on tubular epithelial cells and on glomerular endothelial cells [19].
• We therefore studied the expression of DR3 in human kidney, and report that this death receptor is up-regulated in renal tubular epithelial cells and endothelial cells of some interlobular arteries, in parallel with SODD, during acute transplant rejection [19].
• Furthermore, the expression of DR3 in peripheral blood monocytes was induced after atherogenic stimulation [1].
• Expression of DR3 appears to be restricted to tissues enriched in lymphocytes [20].
• The combination of IL-12 and IL-18 markedly up-regulated DR3 expression in NK cells, whereas it had minimal effect in T cells [23].

Associations of TNFRSF25 with chemical compounds

• The additional N-linked glycan on mutant DR3 molecules isolated from the 10.24.6 cell line, which interferes with DM-enhanced CLIP release from DR3 in vitro, also affects the DM-DR interaction [24].
• The C4A gene deletion was associated with HLA-A1, B8, DR3 in all but 1 patient who was HLA-DR3 negative [25].
• Reticulin-antibody-positive relatives with or without jejunal mucosal atrophy were genetically similar to the probands of the families (DR3 gene frequencies 55.3%-60.0%) [26].
• Like most DR3-type VD response elements, both IP9s are preferentially bound by VDR-RXR heterodimers with a 5'-RXR-VDR-3' polarity, whose transcriptional activity can be enhanced by costimulation with 9-cis retinoic acid [27].
• VDR is functionally active in ATRA-treated Kasumi-1 cells because it efficiently heterodimerizes with retinoid X receptor, binds to a DR3-type vitamin D-responsive element, and activates the transcription of a vitamin D-responsive element-regulated reporter gene [28].

Physical interactions of TNFRSF25

• Several other members of the TNF superfamily, including Fas and death receptors (DR)-3, -4, and -5, also contain intracellular death domains, but SODD only interacts with the death domain of DR3 [19].
• Finally, cells isolated from WSL-1/TRAMP knockout mice are shown to retain their ability to interact with TWEAK [29].

Regulatory relationships of TNFRSF25

• These data suggest that TL1A and DR3 is involved in atherosclerosis via the induction of pro-inflammatory cytokines/chemokines and decreasing plaque stability by inducing extracellular matrix degrading enzymes [1].
• IL-12 plus IL-18 up-regulated DR3 expression in CCR9(+)CD4+ T cells but had negligible effect on CCR9(-)CD4+ T cells [30].
• DR3 is capable of inducing both NF-kappa B activation and apoptosis when overexpressed in mammalian cells, although its ligand has not yet been identified [3].
• Neuroblastoma cell lines with 1p deletion and MYCN-amplification expressed significantly lower levels of Apo-3 (P=0.009 and P=0.03, respectively) compared with neuroblastoma cell lines without 1p deletion or MYCN-amplification [31].

Other interactions of TNFRSF25

• This protein, WSL-1, is most similar to TNFR1 itself, particularly in the death-domain region [11].
• Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis [1].
• However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex [21].
• Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-kappaB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-kappaB activation was responsible for resistance to apoptosis in these cells [21].
• Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B [2].

Analytical, diagnostic and therapeutic context of TNFRSF25

• Duplication of at least a portion of the DR3 gene, including the extracellular and transmembrane regions but not the cytoplasmic domain, was demonstrated by both fluorescence in situ hybridization and genomic Southern blotting [3].
• Death receptors (Fas, TNFR-2, DR3, and TRAIL receptors) induce apoptosis upon ligation to cognate ligands or ectopic expression [32].
• By indirect immunofluorescence and immunoperoxidase imaging and with gel filtration column chromatography, we observed rapid aggregation at the cell surface and the appearance of high molecular weight protein complexes primarily involving DR3, and DR3 and DR4 after camptothecin and VP-16 treatment, respectively [33].
• HLA typing showed HLA-DR3 in 61% of patients (controls 22%, Pc less than 0.005) and the combination of DR3, DR4 in 43% (controls 3%, Pc less than 0.00001) [34].
• To determine whether expression of DR was required for melanoma cells to be stimulatory, we first treated a stimulating cell line of DR3 allospecificity with anti-DR3-specific serum and demonstrated marked inhibition of its capacity to provoke blastogenesis [35].

References