Makindo Medical Notes

Tumour Necrosis Factor (TNF) is a cytokine involved in systemic inflammation and is part of the body's immune response. It plays a crucial role in the regulation of immune cells, inflammation, and apoptosis (programmed cell death). TNF is primarily produced by activated macrophages, although other cells such as lymphocytes, natural killer (NK) cells, and fibroblasts can also produce it.

Structure and Types of TNF

• Structure:
  • TNF is a trimeric protein composed of three identical monomers.
  • Each monomer has a characteristic beta-sheet structure.
• Types:
  • TNF-alpha:
    • The most well-known and studied form of TNF.
    • Primarily involved in inflammatory and immune responses.
  • TNF-beta (Lymphotoxin):
    • Produced by lymphocytes.
    • Involved in the development of lymphoid organs and regulation of immune responses.

Production and Release of TNF

• TNF is produced in response to various stimuli:
  • Bacterial lipopolysaccharides (LPS).
  • Viral infections.
  • Inflammatory signals from other cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6).
• Produced mainly by macrophages, but also by T cells, NK cells, and other cell types.
• Released in both a membrane-bound form and a soluble form after being cleaved by the enzyme TNF-alpha converting enzyme (TACE).

Functions of TNF

• Inflammation:
  • Induces the production of other pro-inflammatory cytokines (e.g., IL-1, IL-6).
  • Promotes the expression of adhesion molecules on endothelial cells, facilitating leukocyte migration to sites of infection or injury.
  • Stimulates the acute phase response, including the production of acute phase proteins by the liver.
• Apoptosis:
  • Can induce apoptosis in certain cells through the activation of death receptors.
  • Plays a role in eliminating cancerous or infected cells.
• Immune Regulation:
  • Modulates the activity of various immune cells, including T cells, B cells, and NK cells.
  • Enhances the microbicidal activity of macrophages.
• Tumour Suppression:
  • Named for its ability to cause necrosis of certain tumours in vivo.
  • Inhibits tumourigenesis by promoting the death of cancer cells and inhibiting their proliferation.
• Metabolic Effects:
  • Involved in the regulation of insulin resistance and lipid metabolism.
  • High levels of TNF are associated with metabolic disorders, such as obesity and type 2 diabetes.

Regulation of TNF Activity

• Receptors:
  • TNF exerts its effects through two main receptors:
    • TNF Receptor 1 (TNFR1): Expressed on most tissues and mediates many of the pro-inflammatory and apoptotic effects of TNF.
    • TNF Receptor 2 (TNFR2): Primarily expressed on immune cells and endothelial cells, involved in immune regulation and tissue regeneration.
• Soluble TNF Receptors:
  • Circulate in the blood and can bind to TNF, neutralizing its activity and modulating its effects.
• Anti-inflammatory Cytokines:
  • Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) can inhibit TNF production and activity.
• Pharmacological Inhibitors:
  • TNF inhibitors, such as monoclonal antibodies (e.g., infliximab, adalimumab) and soluble TNF receptor fusion proteins (e.g., etanercept), are used to treat inflammatory diseases like rheumatoid arthritis and inflammatory bowel disease.

Clinical Relevance

• Rheumatoid Arthritis:
  • TNF plays a significant role in the pathogenesis of rheumatoid arthritis, promoting inflammation and joint damage.
  • TNF inhibitors are effective in reducing symptoms and slowing disease progression.
• Inflammatory Bowel Disease:
  • TNF is involved in the inflammatory processes underlying Crohn's disease and ulcerative colitis.
  • TNF inhibitors are used to manage and induce remission in these conditions.
• Sepsis:
  • Excessive production of TNF during sepsis can lead to systemic inflammation, organ failure, and death.
  • Managing TNF levels is critical in the treatment of sepsis, although the use of TNF inhibitors in sepsis is still under investigation.
• Cancer:
  • While TNF has tumouricidal properties, chronic inflammation induced by TNF can also promote tumourigenesis.
  • Understanding TNF's dual role in cancer is important for developing effective therapies.
• Metabolic Disorders:
  • Elevated TNF levels are associated with insulin resistance and metabolic syndrome.
  • Targeting TNF may have therapeutic potential in managing metabolic disorders.

Summary

Tumour Necrosis Factor (TNF) is a crucial cytokine involved in inflammation, immune regulation, apoptosis, and tumour suppression. It plays significant roles in various physiological and pathological processes, including rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, and metabolic disorders. Understanding TNF's functions and regulation is essential for developing targeted therapies for these conditions.