TNFrelated

TNF-related refers to cytokines and receptors that belong to the tumor necrosis factor (TNF) superfamily. This family includes TNF-α, lymphotoxin-α (TNF-β), and a broad group of ligands such as RANKL (TNFSF11) and TRAIL (TNFSF10), as well as their receptors (TNFRSF proteins). Members are typically type II transmembrane proteins that can exist as membrane-bound trimers and can be cleaved to soluble forms by proteases such as ADAM17.

Signaling in the TNF-related system is initiated when a TNF-family ligand binds to its receptor, leading to the assembly of signaling complexes that can activate NF-κB and MAPK pathways, promoting inflammatory gene expression and cell survival. In certain cellular contexts, signaling can also trigger caspase-dependent apoptosis or necroptosis. Two principal receptors drive many responses: TNFR1 (p55), which is ubiquitously expressed and contains a death domain capable of promoting apoptosis, and TNFR2 (p75), which is more restricted in expression and tends to modulate immune cell activation and regulatory T cell function. The outcome of signaling depends on ligand availability, receptor expression, and cellular context.

Physiological roles of TNF-related signaling include regulation of innate and adaptive immunity, lymphoid organ development, hematopoiesis, and tissue remodeling. Dysregulated signaling is associated with chronic inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, making TNF a prominent therapeutic target in these conditions.

Therapeutically, blocking TNF signaling with monoclonal antibodies (infliximab, adalimumab, golimumab, certolizumab) or with soluble receptor fusion proteins (etanercept) reduces inflammation but can increase susceptibility to infections and other adverse effects. Research continues on strategies to modulate TNF pathways with greater specificity to balance efficacy and safety.