Introduction

• TNF-α is a widely studied cytokine initially discovered for its tumor cell killing ability.
• Plays a role in; modulating immune response, inflammation, apoptosis, cell survival, and tissue repair.
• Mainly secreted by stimulated macrophages, also produced by lymphocytes, natural killer cells, and endothelial cells.

Molecular Structure and Production

• Expressed as a 32 kDa transmembrane protein, processed by TACE to form a 20 kDa soluble form.
• Both membrane-bound and soluble forms are bioactive, interacting with TNFR1 (p55) and TNFR2 (p75) receptors.
• Present as a homotrimer; three-dimensional structure is crucial for receptor binding and biological effects.
• Production tightly regulated at multiple levels:
• Transcriptional control
• Post-transcriptional modification
• Membrane trafficking
• Enzymatic processing
• Receptor-mediated feedback mechanisms

Biological Functions and Signalling Pathways

• Essential for proper immune function and tissue homeostasis:
• Immune System Regulation:
• Activation of inflammatory cells
• Enhancement of phagocytosis
• Stimulation of acute phase protein production
• Promotion of adhesion molecule expression
• Cell Death and Survival:
• Induction of apoptosis in certain cell types
• Promotion of cell survival in other contexts
• Regulation of tissue remodelling
• Control of cell differentiation
• Inflammatory Response:
• Initiation of inflammatory cascades
• Recruitment of immune cells to infection sites
• Production of pro-inflammatory mediators
• Regulation of vascular permeability
• Signalling pathways involve multiple downstream effectors, including NF-κB, MAP kinases, and death receptor signalling pathways.

Role in Disease and Clinical Applications

• Implicated in numerous pathological conditions:
• Autoimmune Disorders: Rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis.
• Inflammatory Conditions: Sepsis, acute lung injury, cardiovascular disease, metabolic disorders.
• Cancer: Tumor promotion and progression, cachexia, anti-tumor immunity.
• Important therapeutic target, leading to development of targeted therapies and strategies.

Therapeutic Approaches and Future Perspectives

• Current Treatment Strategies:
• Systemic TNF-α blockade
• Tissue-specific targeting
• Combination therapies
• Biosimilar development
• Emerging Approaches:
• New delivery systems
• Novel molecular targets
• Biomarkers for treatment response
• Tissue-specific effects
• Risks of anti-TNF-α therapy:
• Increased susceptibility to infections
• Reactivation of latent tuberculosis
• Potential development of autoantibodies
• Risk of certain malignancies
• Research focuses on developing specific and safer approaches to TNF-α modulation:
• Understanding tissue-specific effects
• Identifying new therapeutic targets
• Developing more selective inhibitors