Tumor Necrosis Factor: A Double-Edged Sword in Inflammation and Immune Regulation

Molecular Structure and Biosynthesis Pathway

Tumor Necrosis Factor (TNF) is a homotrimeric cytokine composed of 157 amino acids, with a molecular weight of approximately 17 kDa, and serves as a core member of the TNF superfamily. Structurally, each TNF monomer consists of two antiparallel β-sheets forming a characteristic "sandwich" structure, which stabilizes into a trimer via hydrophobic interactions. X-ray crystallography reveals that the TNF trimer induces specific spatial conformations in TNFR1 or TNFR2 upon binding, triggering downstream signaling cascades. TNF is initially expressed as a 26 kDa transmembrane precursor (tmTNF) on the cell surface and is released as a soluble form (sTNF) through proteolytic cleavage by TNF-α-converting enzyme (TACE/ADAM17). Genetically, the TNF gene is located on the short arm of human chromosome 6 (6p21.3), with its promoter region containing multiple transcription factor binding sites, including NF-κB, AP-1, and CREB, which are rapidly activated in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Monocytes, macrophages, and T lymphocytes are the primary sources of TNF. Under LPS stimulation, TNF mRNA levels can increase 50-100-fold within 30 minutes, followed by precise regulation of expression duration via AU-rich element (ARE)-mediated mRNA degradation. Notably, TNF production exhibits significant cell-type specificity: Th1 cells primarily produce sTNF to promote inflammation, while regulatory T cells tend to express tmTNF for immune regulation.

Receptor System and Signal Transduction Network

TNF transmits signals through two transmembrane receptors, TNFR1 (p55/CD120a) and TNFR2 (p75/CD120b), forming a complex cellular response network. TNFR1 is ubiquitously expressed in nearly all nucleated cells, and its signaling exhibits a biphasic pattern: initially, it activates NF-κB and MAPK pathways via the TRADD/RIP1/TRAF2 complex to promote inflammatory cytokine expression and cell survival; later, it induces apoptosis through FADD/caspase-8. This time-dependent functional switch is finely regulated by the subcellular localization and post-translational modifications of receptor complexes, such as the ubiquitination status of RIP1, which determines signaling outcomes. In contrast, TNFR2 expression is more selective (primarily limited to immune cells and endothelial cells) and activates the PI3K/Akt and NF-κB pathways directly via TRAF1/2, playing a key role in tissue repair and immune regulation. Recent studies show that sTNF primarily activates TNFR1-mediated pro-inflammatory responses, while tmTNF more effectively activates TNFR2-mediated pro-survival signals, providing a basis for targeted interventions. Signal regulation involves molecules like the deubiquitinase A20 and the linear ubiquitin chain assembly complex (LUBAC), which act as "molecular brakes" to prevent excessive activation. Notably, cross-regulation exists between TNFR1 and TNFR2, where TNFR2 can inhibit TNFR1 signaling by sequestering TRAF2. This receptor crosstalk adds complexity to the signaling network and explains the differential cellular responses to TNF.

Central Role in Inflammatory Responses

As a key mediator of inflammatory cascades, TNF plays a central role in various acute and chronic inflammatory processes. During infection or tissue injury, TNF initiates inflammation through three mechanisms: upregulating endothelial adhesion molecules (ICAM-1, VCAM-1, and selectins) to promote leukocyte rolling, adhesion, and transendothelial migration; stimulating hepatocytes to produce acute-phase proteins (e.g., C-reactive protein and serum amyloid A); and activating fibroblasts and epithelial cells to release chemokines (IL-8, MCP-1) and other pro-inflammatory cytokines (IL-1, IL-6). At the molecular level, TNF induces the expression of multiple inflammatory mediators via NF-κB, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMP-1/3/9). Animal models demonstrate that TNF knockout mice are completely resistant to LPS-induced shock but exhibit significantly impaired clearance of certain pathogens (e.g., Listeria), highlighting TNF's dual role in host defense. In chronic inflammation, persistent TNF promotes inflammatory cell infiltration and tissue remodeling, such as synovial hyperplasia and bone erosion in rheumatoid arthritis (RA). Clinical studies show that serum TNF levels correlate with disease activity in various inflammatory conditions, reaching >1000 pg/mL in sepsis patients (compared to <10 pg/mL in healthy individuals) and serving as an independent predictor of severity and prognosis. Interestingly, TNF also participates in inflammation resolution by inducing anti-inflammatory factors (e.g., IL-10) and promoting macrophage phenotype switching, a bidirectional regulatory function critical for immune homeostasis.

Pathogenic Mechanisms in Autoimmune Diseases

Aberrant TNF expression is closely linked to the pathogenesis and progression of multiple autoimmune diseases, making it a key therapeutic target. In RA, synovial fluid TNF concentrations can be 100-fold higher than in healthy individuals, driving joint destruction via three mechanisms: enhancing osteoclast differentiation and bone resorption (5-10-fold increase in RANKL expression); inhibiting chondrocyte synthesis of aggrecan (3-fold increase in degradation); and inducing synovial fibroblasts to produce MMPs (especially MMP-3 and MMP-13) that degrade cartilage matrix. Genome-wide association studies (GWAS) identify the -308G>A (rs1800629) polymorphism in the TNF gene promoter as a risk factor for RA, with the A allele increasing TNF transcriptional activity 2-3-fold. In ankylosing spondylitis (AS), tmTNF activates osteogenic differentiation of mesenchymal stem cells via TNFR2, leading to ligament ossification and spinal fusion. In inflammatory bowel disease (IBD), TNF increases intestinal epithelial permeability (60-80% reduction in transepithelial resistance), disrupts tight junction proteins (e.g., occludin and claudin-1/3/5), and promotes Th1/Th17 responses. Systemic lupus erythematosus (SLE) patients exhibit elevated serum TNF levels correlating with disease activity (SLEDAI), though paradoxically, TNF may have protective effects in some SLE models, likely due to stage- and organ-specific roles. In multiple sclerosis (MS), TNF disrupts the blood-brain barrier and activates microglia, yet anti-TNF therapy unexpectedly worsens symptoms, underscoring TNF's spatiotemporal complexity in neuroinflammation.

Clinical Applications and Advances in Anti-TNF Therapy

Anti-TNF therapy has become a milestone in autoimmune disease treatment, with over 7 million patients worldwide receiving these biologics. Clinically used anti-TNF agents fall into three categories: monoclonal antibodies (e.g., adalimumab, infliximab), receptor fusion proteins (etanercept), and PEGylated Fab fragments (certolizumab pegol). These drugs differ significantly in molecular properties and clinical effects: IgG1 monoclonal antibodies (e.g., adalimumab) bind both soluble and membrane-bound TNF, have a ~2-week half-life, and mediate ADCC/CDC via Fc regions, while etanercept (a TNFR2-Fc fusion) primarily neutralizes soluble TNF with a shorter half-life (3-5 days). Clinical trials show anti-TNF therapy improves ACR50 response rates in RA from ~10% (placebo) to 50-60%, with >70% reduction in radiographic progression. In Crohn’s disease, 60-70% of patients achieve clinical remission, with mucosal healing rates increasing 3-4-fold. However, 30-40% of patients experience primary or secondary failure due to anti-drug antibodies (5-15% incidence), alternative inflammatory pathway activation (e.g., IL-17/23 axis), or epigenetic remodeling. Next-generation strategies aim to overcome these limitations: nanobodies (e.g., ozoralizumab) improve tissue penetration; bispecific antibodies (e.g., TNF/IL-17 dual-targeting) block multiple pathways; and prodrug antibodies activate selectively in inflammatory microenvironments. Therapeutic drug monitoring (serum drug levels and anti-drug antibodies) guided dose optimization improves response rates by 15-20%.

Dual Roles in Infection and Cancer

TNF exhibits context-dependent roles in infection defense and tumor immunity. In bacterial infections, TNF enhances macrophage/neutrophil bactericidal activity and promotes granuloma formation to contain pathogens. Anti-TNF therapy increases latent tuberculosis reactivation risk 4-10-fold, underscoring TNF's role in granuloma maintenance. In viral infections, TNF limits replication by inducing apoptosis, though viruses like EBV and HCV evade TNF signaling. In cancer, TNF has dose-dependent biphasic effects: physiological levels activate endothelial cells and cytotoxic T cells for immune surveillance, while chronic overproduction creates a pro-tumor microenvironment (e.g., angiogenesis and immunosuppression). Anti-TNF therapy slightly increases lymphoma risk (standardized incidence ratio [SIR]=1.5-3.0) but has unclear effects on solid tumors. Notably, local high-dose TNF (e.g., isolated limb perfusion) selectively disrupts tumor vasculature, achieving 60-80% response rates in melanoma and sarcoma. Combining TNF blockade with PD-1 inhibitors may enhance efficacy by reducing MDSC/Treg immunosuppression, a hypothesis under clinical investigation.

Future Directions and Therapeutic Prospects

TNF research is advancing toward precision, minimally invasive, and intelligent therapies. Single-cell multi-omics reveal cell-specific TNF functions: myeloid-derived TNF drives inflammation initiation, while lymphocyte-derived TNF favors immune regulation. Emerging strategies include GalNAc-siRNA conjugates targeting macrophage TNF mRNA. Epigenetic studies link TNF locus DNA methylation to treatment response, enabling personalized therapy. Nanomedicine innovations include pH-responsive TNF inhibitors and gold nanoparticle-conjugated TNF antibodies for photothermal synergy. Dual-targeting molecules (e.g., TNF/IL-23 nanobodies) outperform monotherapies in psoriasis models. CRISPR-Cas9-engineered TNF reporter models enable high-throughput drug screening. Clinical applications are expanding to Alzheimer’s disease (2-3-fold elevated TNF), metabolic syndrome, and fibrotic disorders. In the next 5 years, 10-15 novel TNF modulators are expected to enter clinical trials, with AI-guided personalized regimens ushering in a new era of precision medicine.

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