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Project description:The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin β Receptor (LTβR), a core member of the Tumor Necrosis Factor (TNF)/TNF Receptor (TNFR) superfamily is known to play an important role in this process. However, LTβR functions in the pathophysiological alterations and molecular mechanisms of liver regeneration are so far ill-characterized. Interestingly, LTβR / mice suffered from increased and prolonged liver tissue damage after 70 % hepatectomy (PHx), a finding accompanied by elevated alkaline phosphatase levels and deregulated bile acid (BA) homeostasis. Pronounced differences in the expression patterns of genes relevant for BA synthesis and recirculation were observed. Transcriptome analysis revealed a marked disparity in gene expression programs in LTβR / vs. WT liver tissue, where gene ontology (GO) terms related to transcription, gene expression and metabolic pathways were over-represented in the latter. In addition, murinoglobulin 2 (Mug2), a gene product to date not implicated in liver regeneration, was identified as one of the most differentially regulated genes after PHx in WT compared to LTβR / and TNFRp55-/- livers. LTβR and TNFRp55 share downstream signaling elements. TNFRp55 is known to also play an important role in liver regeneration after PHx. Therefore, LTβR / mice were treated with Etanercept to create mice functionally deficient in both signaling pathways. Strikingly, the combined blockade of TNFR and LTβR signaling leads to complete failure of liver regeneration resulting in death within 24 to 48 hours after PHx. LTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signaling renders liver regeneration impossible.
2024-02-25 | GSE74531 | GEO
Project description:The liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin β Receptor (LTβR), a core member of the Tumor Necrosis Factor (TNF)/TNF Receptor (TNFR) superfamily is known to play an important role in this process. However, LTβR functions in the pathophysiological alterations and molecular mechanisms of liver regeneration are so far ill-characterized. Interestingly, LTβR / mice suffered from increased and prolonged liver tissue damage after 70 % hepatectomy (PHx), a finding accompanied by elevated alkaline phosphatase levels and deregulated bile acid (BA) homeostasis. Pronounced differences in the expression patterns of genes relevant for BA synthesis and recirculation were observed. Transcriptome analysis revealed a marked disparity in gene expression programs in LTβR / vs. WT liver tissue, where gene ontology (GO) terms related to transcription, gene expression and metabolic pathways were over-represented in the latter. In addition, murinoglobulin 2 (Mug2), a gene product to date not implicated in liver regeneration, was identified as one of the most differentially regulated genes after PHx in WT compared to LTβR / and TNFRp55-/- livers. LTβR and TNFRp55 share downstream signaling elements. TNFRp55 is known to also play an important role in liver regeneration after PHx. Therefore, LTβR / mice were treated with Etanercept to create mice functionally deficient in both signaling pathways. Strikingly, the combined blockade of TNFR and LTβR signaling leads to complete failure of liver regeneration resulting in death within 24 to 48 hours after PHx. LTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signaling renders liver regeneration impossible.
2024-02-25 | GSE67263 | GEO
Project description:Cooperative role of Lymphotoxin Beta Receptor and Tumor Necrosis Factor Receptor p55 in murine liver regeneration
| PRJNA300670 | ENA
Project description:The formation of germinal centers (GCs) represents a crucial step in the humoral immune response. Recent studies using gene-targeted mice have revealed that the cytokines tumor necrosis factor (TNF), lymphotoxin (LT) alpha, and LTbeta, as well as their receptors TNF receptor p55 (TNFRp55) and LTbetaR play essential roles in the development of GCs. To establish in which cell types expression of LTbetaR, LTbeta, and TNF is required for GC formation, LTbetaR-/-, LTbeta-/-, TNF-/-, B cell-deficient (BCR-/-), and wild-type mice were used to generate reciprocal or mixed bone marrow (BM) chimeric mice. GCs, herein defined as peanut agglutinin-binding (PNA+) clusters of centroblasts/centrocytes in association with follicular dendritic cell (FDC) networks, were not detectable in LTbetaR-/- hosts after transfer of wild-type BM. In contrast, the GC reaction was restored in LTbeta-/- hosts reconstituted with either wild-type or LTbetaR-/- BM. In BCR-/- recipients reconstituted with compound LTbeta-/-/BCR-/- or TNF-/-/BCR-/- BM grafts, PNA+ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent. Thus, development of splenic FDC networks depends on expression of LTbeta and TNF by B lymphocytes and LTbetaR by radioresistant stromal cells.
| S-EPMC1887694 | biostudies-literature
Project description:In the early 1990s, it has been described that LTα and LTβ form LTα2β and LTαβ2 heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ2-LTβR system has been intensively studied while the LTα2β-TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα2β-TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα2β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα2β (memLTα2β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα2β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.
| S-EPMC8024344 | biostudies-literature
Project description:Gene expresion comperison of p55/p75 double knock and it control B57B6 identified a number of inflammatory genes and cytokines genes play important roles in this study. TNFa has both pro-inflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in SLE-prone (NZB x NZW)F1 mice has been established, it remains uncertain whether this effect segregates at the individual TNF receptors (TNFR). We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNF receptor 1, in TNF receptor 2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4+ T lymphocytes, especially activated memory (CD44highCD62Llow) CD4+ T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNF receptor alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNFa-mediated signaling was highly deleterious to the host in the NZM 2328 SLE model. These observations may have profound ramifications for the use of TNF- and TNF receptor-antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.
2009-12-06 | GSE13855 | GEO
Project description:BACKGROUND: Tumor necrosis factors, TNF and lymphotoxin-? (LT), are cytokines that bind to two receptors, TNFR1 and TNFR2 (TNF-receptor 1 and 2) to trigger their signaling cascades. The exact mechanism of ligand-induced receptor activation is still unclear. It is generally assumed that three receptors bind to the homotrimeric ligand to trigger a signaling event. Recent evidence, though, has raised doubts if the ligand:receptor stoichiometry should indeed be 3:3 for ligand-induced cellular response. We used molecular dynamics simulations, elastic network models, as well as MM/PBSA to analyze this question. RESULTS: Applying MM/PBSA methodology to different stoichiometric complexes of human LT-(TNFR1)n=1,2,3 the free energy of binding in these complexes has been estimated by single-trajectory and separate-trajectory methods. Simulation studies rationalized the favorable binding energy in the LT-(TNFR1)1 complex, as evaluated from single-trajectory analysis to be an outcome of the interaction of cysteine-rich domain 4 (CRD4) and the ligand. Elastic network models (ENMs) help to associate the difference in the global fluctuation of the receptors in these complexes. Functionally relevant transformation associated with these complexes reveal the difference in the dynamics of the receptor when free and in complex with LT. CONCLUSIONS: MM/PBSA predicts complexes with a ligand-receptor molar ratio of 3:1 and 3:2 to be energetically favorable. The high affinity associated with LT-(TNFR1)1 is due to the interaction between the CRD4 domain with LT. The global dynamics ascertained from ENMs have highlighted the differential dynamics of the receptor in different states.
| S-EPMC3412742 | biostudies-literature
Project description:ObjectiveMouse aorta smooth muscle cells (SMC) express tumor necrosis factor receptor superfamily member 1A (TNFR-1) and lymphotoxin beta-receptor (LTbetaR). Circumstantial evidence has linked the SMC LTbetaR to tertiary lymphoid organogenesis in hyperlipidemic mice. Here, we explored TNFR-1 and LTbetaR signaling in cultured SMC.Methods and resultsTNFR-1 signaling activated the classical RelA NF-kappaB pathway, whereas LTbetaR signaling activated the classical RelA and alternative RelB NF-kappaB pathways, and both signaling pathways synergized to enhance p100 inhibitor processing to the p52 subunit of NF-kappaB. Microarrays showed that simultaneous TNFR-1/LTbetaR activation resulted in elevated mRNA encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Importantly, SMC acquired features of lymphoid tissue organizers, which control tertiary lymphoid organogenesis in autoimmune diseases through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. TNFR-1/LTbetaR cross-talk resulted in augmented secretion of lymphorganogenic chemokine proteins. Supernatants of TNFR-1/LTbetaR-activated SMC markedly supported migration of splenic T cells, B cells, and macrophages/dendritic cells. Experiments with ltbr(-/-) SMC indicated that LTbetaR-RelB activation was obligatory to generate the lymphoid tissue organizer phenotype.ConclusionsSMC may participate in the formation of tertiary lymphoid tissue in atherosclerosis by upregulation of lymphorganogenic chemokines involved in T-lymphocyte, B-lymphocyte, and macrophage/dendritic cell attraction.
| S-EPMC2874749 | biostudies-literature
Project description:Intraperitoneal (i.p.) infection with a high dose of a highly virulent Ehrlichia strain (IOE) results in a toxic shock-like syndrome characterized by severe liver injury and systemic overproduction of tumor necrosis factor alpha (TNF-alpha) by CD8+ T cells. We examined the role of TNF-alpha and TNF receptors in high-dose-IOE-induced shock/liver injury. TNF receptor (TNFR) I/II-/- mice lacking both the p55 and p75 receptors for this cytokine were more resistant to IOE-induced liver injury than their wild-type background controls. TNFR I/II-/- mice survived longer, dying between 15 and 18 days, with evidence of mild liver necrosis/apoptosis. In contrast, wild-type mice were not rescued from the lethal effect of IOE by TNF-alpha neutralization. TNF-alpha-depleted mice developed severe liver injury and succumbed to disease between days 9 and 11 postinfection, similar to sham-treated, infected wild-type mice. Although IFN-gamma production in the spleens of IOE-infected TNFR I/II-/- and TNF-alpha-depleted mice was higher than that detected in wild-type controls, these mice had higher bacterial burdens than infected controls. Following high-dose IOE challenge, TNFR I/II-/- and TNF-alpha-depleted mice have an early increase in IL-10 levels in sera and spleens, which was produced mainly by adherent spleen cells. In contrast, a late burst of interleukin-10 (IL-10) was observed in control mice. Nonadherent spleen cells were the major source of IL-10 in IOE-infected wild-type mice. We conclude that TNFR I/II and TNF-alpha participate in Ehrlichia-induced shock and host defense by regulating liver injury and controlling ehrlichial burden. Our data suggest that fatal ehrlichiosis could be a multistep process, where TNF-alpha is not solely responsible for mortality.
| S-EPMC1418656 | biostudies-literature
Project description:The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm(3)) was significantly reduced compared with WT (19.7±3.4 mm(3)) and p75 (-/-) mice (20.9±3.2 mm(3)). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI.
| S-EPMC3734767 | biostudies-other