Makindo Medical Notes

🧪 Tumour Necrosis Factor (TNF) is a pro-inflammatory cytokine central to host defence and immune regulation. Although essential for fighting infection and controlling cancer, excessive or dysregulated TNF drives many chronic inflammatory diseases.

Structure and Types of TNF

• 🔬 Structure:
  • TNF is a trimeric protein (three identical monomers).
  • Each monomer has a characteristic beta-sheet structure.
• 🧬 Types:
  • TNF-alpha → best known form, produced by macrophages, drives inflammation & immune responses.
  • TNF-beta (Lymphotoxin) → produced by lymphocytes, key for lymphoid organ development & immune regulation.

Production and Release

• 🦠 Produced in response to bacterial LPS, viral infection, or other cytokines (IL-1, IL-6).
• 🧩 Main producers = macrophages, but also T cells, NK cells, fibroblasts.
• 🧲 Exists in:
  • Membrane-bound form
  • Soluble form (after cleavage by TNF-alpha converting enzyme, TACE)

Functions of TNF

• 🔥 Inflammation: Induces IL-1, IL-6, adhesion molecules → leukocyte recruitment; triggers acute phase response.
• 💀 Apoptosis: Activates death receptors → removes infected/cancerous cells.
• 🛡️ Immune Regulation: Shapes T, B, NK cell activity; boosts macrophage killing.
• 🎯 Tumour Suppression: Can induce necrosis of tumours; inhibits cancer proliferation.
• ⚖️ Metabolism: Contributes to insulin resistance & lipid dysregulation; high TNF linked to obesity & T2DM.

Regulation of TNF Activity

• 📡 Receptors:
  • TNFR1 – on most tissues; mediates pro-inflammatory/apoptotic effects.
  • TNFR2 – on immune/endothelial cells; regulates immunity & repair.
• 💧 Soluble TNF Receptors: Circulate in blood, bind TNF, reducing activity.
• 🧴 Anti-inflammatory Cytokines: IL-10, TGF-beta suppress TNF activity.
• 💊 Pharmacological Inhibitors:
  • Monoclonal antibodies: infliximab, adalimumab
  • Receptor fusion protein: etanercept
  • Indications: RA, ankylosing spondylitis, psoriasis, IBD

📝 Exam tip: TNF inhibitors = “biologics” used when standard DMARDs fail in rheumatoid arthritis.

Clinical Relevance

• 🦴 Rheumatoid Arthritis: TNF drives synovial inflammation & joint destruction → TNF blockers improve outcomes.
• 💩 Inflammatory Bowel Disease: (Crohn’s, UC) → anti-TNF agents induce remission, reduce surgery rates.
• 🧬 Sepsis: Excess TNF → cytokine storm, organ failure. Trials of TNF inhibitors ongoing.
• 🎗️ Cancer: Dual role: tumour killing vs cancer-promoting inflammation.
• ⚡ Metabolic Disease: High TNF linked to insulin resistance, metabolic syndrome, obesity-related inflammation.

Summary

🌟 TNF = double-edged sword: Essential for immunity & tumour defence, but excessive TNF drives chronic inflammation, autoimmunity, sepsis, and metabolic disease. Targeted TNF inhibitors have revolutionised the treatment of RA, IBD, psoriasis, and other inflammatory conditions.