TNFSF14 Human

What is TNFSF14 and what are its alternative names in scientific literature?

TNFSF14 is a cytokine belonging to the TNF superfamily with a molecular mass of approximately 26.4 kilodaltons. In scientific literature, it's also known as:

• LIGHT (homologous to Lymphotoxin, exhibits Inducible expression and competes with HSV Glycoprotein D for binding to HVEM)

• CD258

• Tumor necrosis factor ligand superfamily member 14

• HVEML

Methodologically, researchers identify TNFSF14 through genomic analysis, protein expression studies, and functional assays examining its interactions with specific receptors. Orthologs exist in multiple species including mouse, rat, monkey, canine, and porcine models, facilitating comparative studies .

What are the primary receptors for TNFSF14 and their signaling mechanisms?

TNFSF14 primarily interacts with two receptors:

• TNFRSF14 (also known as HVEM)

• Lymphotoxin β receptor (LTβR)

These interactions involve specific binding regions with hydrogen bonds, CH-π interactions, and nonpolar interactions. Methodologically, researchers study these interactions through:

• Crystallography studies

• Protein-protein interaction assays

• Mutagenesis experiments

• Downstream signaling cascade analysis

Activation of these receptors triggers multiple signaling pathways related to inflammation, tissue remodeling, and metabolism, including AKT phosphorylation and AMPK activation pathways .

How should researchers properly select antibodies for TNFSF14 detection?

Selecting appropriate antibodies for TNFSF14 requires consideration of:

• Application specificity: Anti-TNFSF14 antibodies are optimized for different applications:

  • Western blot analysis

  • Immunohistochemistry (IHC-p and IHC-fr)

  • Flow cytometry (FCM)

  • ELISA (capture and detection)

• Species reactivity: Available antibodies target human, mouse, and rat TNFSF14 with varying cross-reactivity

• Conjugation requirements: Options include:

  • Unconjugated antibodies

  • Biotin-conjugated

  • Fluorophore-conjugated (Cy3, Dylight488)

Methodologically, researchers should validate antibody specificity through positive and negative controls, titration experiments, and cross-reactivity testing in their specific experimental systems.

What mechanisms underlie TNFSF14's role in fibrotic diseases?

TNFSF14 functions as a pro-fibrotic factor through several interconnected mechanisms:

• Upregulation of Sphk1 expression: In renal fibrosis, TNFSF14 significantly increases sphingosine kinase 1 (Sphk1) expression, a critical molecule in fibrotic pathogenesis

• Enhancement of inflammatory cytokine production: TNFSF14 deficiency leads to marked reduction in inflammatory cytokine expression in UUO (unilateral ureteral obstruction) mice

• Promotion of tissue remodeling: In pulmonary tissues, TNFSF14 contributes to characteristic tissue remodeling seen in asthma and idiopathic pulmonary fibrosis

Methodologically, researchers have established these mechanisms through:

• Comparative studies between wild-type and Tnfsf14 knockout mice

• In vitro administration of recombinant TNFSF14 to primary cell cultures

• Expression analysis of fibrosis markers and inflammatory mediators

• Histopathological examination of fibrotic lesions

How does TNFSF14 contribute to atherosclerosis and cardiovascular risk?

TNFSF14 has emerged as a significant factor in atherosclerosis pathogenesis and cardiovascular risk:

Research methodology included:

• Quartile stratification of patients based on TNFSF14 levels

• Kaplan-Meier analysis showing significant survival differences between highest and lowest quartiles

• Multivariate Cox proportional hazard regression analysis adjusting for relevant cardiovascular risk factors

These findings demonstrate that TNFSF14 independently predicts cardiovascular events in CAD patients, suggesting its potential as a prognostic biomarker .

What experimental evidence connects TNFSF14 to metabolic disorders?

Research has identified TNFSF14-derived peptides as potential therapeutic agents for metabolic disorders through multiple lines of experimental evidence:

• In vitro insulin signaling enhancement: TNFSF14 peptides (particularly peptides 6, 7, 9, and 10) significantly increase insulin signaling in L6 skeletal muscle myotubes, as evidenced by enhanced AKT phosphorylation

• Increased fatty acid oxidation:

  • In skeletal muscle: Peptides 7 and 9 increased fatty acid oxidation signaling

  • In liver tissue: Peptide 7 enhanced AMPK phosphorylation

• In vivo glucose homeostasis improvement: Administration of Peptide 7 in high-fat diet (HFD) models demonstrated:

  • Decreased hyperglycemia

  • Improved glucose tolerance

  • Reduced SGLT2 expression

These findings collectively suggest that TNFSF14-derived molecules positively regulate glucose and lipid metabolism, offering novel therapeutic potential for obesity and related metabolic disorders .

What animal models are most effective for studying TNFSF14's role in different disease processes?

Based on published research, the following animal models have proven effective for studying TNFSF14's diverse roles:

Methodologically, researchers should:

• Consider both genetic approaches (Tnfsf14 knockout) and pharmacological interventions (peptide administration)

• Include appropriate controls and sufficient sample sizes

• Evaluate multiple parameters (histological, molecular, functional)

How should researchers design experiments to differentiate TNFSF14's effects on its different receptors?

Designing experiments that differentiate TNFSF14's effects based on receptor specificity requires sophisticated approaches:

• Receptor-specific knockout models:

  • TNFRSF14 (HVEM) knockout

  • LTβR knockout

  • Double receptor knockout comparisons

• Receptor-selective ligands/antagonists:

  • Synthesize TNFSF14-derived peptides with enhanced binding specificity to either TNFRSF14 or LTβR

  • Utilize receptor-specific blocking antibodies

• Structure-function analysis:

  • Identify binding regions using hydrogen bonds, CH-π interactions, and nonpolar interactions data

  • Create interaction maps for each receptor-ligand complex

• Cell-type specific approaches:

  • Use cell systems expressing predominantly one receptor

  • Employ conditional receptor knockout in specific tissues

Methodologically, researchers should validate receptor specificity through binding assays, competition studies, and downstream signaling analysis specific to each receptor pathway.

How can researchers reconcile TNFSF14's apparently contradictory roles in different tissues and disease states?

TNFSF14 exhibits context-dependent effects across different tissues and disease states, presenting a complex research challenge:

• Receptor expression profiling:

  • Map tissue-specific distribution of TNFRSF14 vs. LTβR

  • Analyze receptor expression changes during disease progression

  • Identify co-receptor or signaling partners unique to each tissue context

• Signaling pathway discrimination:

  • In fibrosis: Focus on Sphk1 upregulation pathway

  • In metabolism: Examine AKT and AMPK phosphorylation pathways

  • In inflammation: Analyze cytokine production cascades

• Temporal dynamics analysis:

  • Acute vs. chronic TNFSF14 expression effects

  • Early disease initiation vs. later progression stages

  • Resolution and repair phase contributions

Research groups should employ comprehensive multi-omics approaches (transcriptomics, proteomics, metabolomics) in tissue-specific contexts, with careful attention to disease stage and microenvironment factors to reconcile these apparently contradictory roles .

What are the most significant technical challenges in translating TNFSF14 research from animal models to human applications?

Translating TNFSF14 research to human applications faces several technical challenges:

• Interspecies variations:

  • Human TNFSF14 shares approximately 80% homology with mouse ortholog

  • Receptor binding kinetics and downstream signaling may differ

  • Disease processes develop over different timescales

• Delivery and pharmacokinetics:

  • Peptide stability and half-life in circulation

  • Tissue-specific targeting challenges

  • Blood-brain barrier penetration for neurological applications

• Safety considerations:

  • Potential immunogenicity of TNFSF14-derived therapeutics

  • Off-target effects due to receptor expression in multiple tissues

  • Dose-dependent transition from therapeutic to inflammatory effects

Methodologically, researchers should:

• Develop humanized mouse models

• Conduct comparative studies with human samples

• Establish in vitro systems using patient-derived cells

• Design tissue-specific delivery systems for TNFSF14-targeting agents

What methodological approaches should be employed to develop TNFSF14-targeted therapies?

Developing effective TNFSF14-targeted therapies requires systematic methodological approaches:

• Target identification and validation:

  • Determine whether inhibition or enhancement of TNFSF14 is desired for specific conditions

  • Validate target in multiple preclinical models

  • Establish clear biomarkers of target engagement

• Therapeutic modality selection:

  • TNFSF14-derived peptides (for metabolic disorders)

  • Receptor-specific antibodies

  • Small molecule modulators of TNFSF14-receptor interactions

  • Gene therapy approaches to modulate TNFSF14 expression

• Optimization pipeline:

  • Structure-activity relationship studies

  • PK/PD modeling

  • Formulation development for stability

  • Tissue-specific delivery strategies

• Translational considerations:

  • Patient stratification strategies based on TNFSF14 levels

  • Combination therapy approaches

  • Biomarker development for treatment response

For peptide-based approaches specifically, researchers have demonstrated success through peptide identification, optimization, and functional testing in both in vitro and in vivo systems .

How can TNFSF14 biomarker development be optimized for clinical application?

Optimizing TNFSF14 as a clinical biomarker requires rigorous methodological approaches:

• Standardization of measurement:

  • Develop and validate standardized ELISA or other quantitative assays

  • Establish reference ranges in healthy populations

  • Account for pre-analytical variables affecting measurement

• Clinical validation strategy:

  • Large-scale, multicenter prospective studies (as demonstrated in the 894-patient CAD study)

  • Independent validation cohorts (as shown in the 126-patient multivessel CAD cohort)

  • Longitudinal sampling to assess temporal changes

• Statistical and analytical considerations:

  • Determine optimal cut-off values using ROC analysis

  • Apply multivariate analysis to control for confounding factors

  • Evaluate additive value to existing biomarker panels

• Practical implementation aspects:

  • Sample stability and storage requirements

  • Point-of-care testing feasibility

  • Cost-effectiveness analysis for routine clinical use

Research has already demonstrated TNFSF14's potential as a cardiovascular risk biomarker, with significant predictive value for clinical outcomes independent of traditional risk factors (adjusted hazard ratio: 1.14; 95% CI: 1.04-1.25) .