What is Tumor Necrosis Factor (TNF) and which cells release it?

What is Tumor Necrosis Factor (TNF) and Which Cells Release It?

TNF (Tumor Necrosis Factor) is a proinflammatory cytokine produced primarily by activated macrophages and monocytes, though a wide variety of cell types including keratinocytes, epithelial cells, and lymphocytes also release it. 1

Cellular Sources of TNF

Primary producers:

• Monocytes and macrophages are the predominant cellular sources of TNF-α 1, 2
• Activated T lymphocytes produce TNF as part of the adaptive immune response 3, 4
• Keratinocytes (skin cells) produce TNF and contribute to inflammatory skin conditions like psoriasis 1
• Epithelial cells release TNF during acute inflammation 1

Secondary producers:

• Neutrophils can produce TNF during inflammatory responses 1
• Natural killer (NK) cells contribute to TNF production 1
• Various other immune cells release TNF when activated 5

Forms and Mechanisms of TNF

TNF exists in two biologically active forms: 1

• Transmembrane TNF (tmTNF): Cell surface-bound precursor form that remains attached to the cell membrane
• Soluble TNF (sTNF): Released into circulation after enzymatic cleavage from tmTNF

Both forms bind to two distinct receptors: 1, 2

• TNF receptor 1 (TNFR1, p55)
• TNF receptor 2 (TNFR2, p75)

Primary Functions of TNF

Proinflammatory activities: 1

• Promotes leukocyte extravasation (movement of white blood cells from blood vessels into tissues)
• Induces fever through direct effects on the central nervous system 6
• Promotes vasodilation to increase blood flow to inflamed areas

Immune modulation: 1

• Up-regulates other inflammatory mediators through NF-κB activation, which promotes inflammation 1, 7
• Controls intracellular infections including mycobacteria and certain fungi 1
• Activates neutrophils and eosinophils as part of the immune response 5

Cellular effects: 2, 7

• Can induce cell apoptosis (programmed cell death) depending on cellular context
• Modulates expression of adhesion molecules (E-selectin, ICAM-1) responsible for leukocyte migration 2
• Regulates production of other cytokines including IL-6 2

Metabolic effects: 1

• Alters lipid metabolism 5
• Can cause cachexia (wasting syndrome) in chronic disease states 8, 5

Pathological Roles

TNF plays a central role in multiple disease states: 1

• Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis (elevated TNF in affected joints and tissues) 1, 9
• Psoriasis (elevated TNF in involved skin) 1
• Inflammatory bowel disease 9

Excessive TNF production contributes to: 6, 8

• Septic shock through dysregulated inflammatory response (though TNF does not directly stimulate septic shock itself) 6
• Autoimmune diseases 8
• Tumor cachexia 8, 5

Clinical Significance

TNF inhibitors are FDA-approved treatments for multiple inflammatory conditions, including etanercept, infliximab, and adalimumab, which work by binding TNF-α and preventing its interaction with cell surface receptors 9, 2

Critical warning: Blocking TNF significantly increases risk of serious infections, particularly tuberculosis reactivation, invasive fungal infections, and nontuberculous mycobacterial infections, because TNF is essential for controlling intracellular pathogens 1, 9