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Target: TNF


Research on Tumor Necrosis Factor (TNF)

1. Target Summary:

Tumor Necrosis Factor (TNF) is a pro-inflammatory cytokine primarily produced by macrophages, T cells, and other immune cells. It plays a crucial role in the regulation of immune responses, inflammation, and apoptosis. TNF is implicated in various autoimmune diseases, including rheumatoid arthritis, Crohn's disease, psoriasis, and ankylosing spondylitis. Elevated levels of TNF are associated with chronic inflammation and tissue damage, making it a significant target for therapeutic intervention.

2. Mechanism:

TNF exerts its effects through two main receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Upon binding to these receptors, TNF activates several intracellular signaling pathways, including:
  • NF-κB Pathway: Activation of NF-κB leads to the transcription of pro-inflammatory cytokines, chemokines, and adhesion molecules, promoting inflammation and immune cell recruitment.
  • MAPK Pathway: This pathway is involved in cell proliferation, differentiation, and survival. It includes ERK, JNK, and p38 MAPK, which mediate various cellular responses to TNF.
  • Apoptosis Pathway: TNF can induce apoptosis through the activation of caspases, particularly in cells expressing TNFR1.
The diverse effects of TNF are mediated by the balance between pro-inflammatory and anti-inflammatory signals, which can vary based on the cellular context and the presence of other cytokines (Tracey et al., 2008; Mitoma et al., 2018).

3. Approved Drugs:

Several TNF inhibitors have been approved for clinical use, including:
  • Adalimumab (Humira): A fully human monoclonal antibody that neutralizes TNF-alpha.
  • Infliximab (Remicade): A chimeric monoclonal antibody that binds to TNF-alpha.
  • Etanercept (Enbrel): A soluble TNF receptor fusion protein that acts as a decoy receptor.
  • Certolizumab pegol (Cimzia): A PEGylated Fab' fragment of a monoclonal antibody against TNF-alpha.
  • Golimumab (Simponi): A human monoclonal antibody that inhibits TNF-alpha (Gerriets et al., 2025).

4. Hypotheses:

  • Hypothesis 1: TNF plays a critical role in the pathogenesis of autoimmune diseases, and its inhibition can lead to improved clinical outcomes.
  • Hypothesis 2: Different TNF inhibitors may exhibit varying efficacy based on their mechanisms of action and pharmacokinetic properties, suggesting that personalized treatment approaches may enhance therapeutic outcomes (Mitoma et al., 2018).
  • Hypothesis 3: The long-term use of TNF inhibitors may lead to changes in immune system dynamics, potentially increasing the risk of infections or malignancies.

5. Validation:

The role of TNF in inflammation and autoimmune diseases is well-established through numerous clinical studies and trials. For instance, TNF inhibitors have shown significant efficacy in reducing disease activity in rheumatoid arthritis and inflammatory bowel disease (Olesen et al., 2016). Clinical guidelines recommend TNF inhibitors for patients who do not respond to conventional therapies, further validating their therapeutic potential (ACR Guidelines, 2021).

6. Clinical Trials:

Recent clinical trials have focused on the efficacy and safety of TNF inhibitors in various conditions. For example, studies have demonstrated the effectiveness of adalimumab in treating hidradenitis suppurativa and Crohn's disease (Goldburg et al., 2020; Liu et al., 2022). Ongoing trials continue to explore the long-term effects and optimal use of TNF inhibitors in diverse patient populations.

7. Involved Pathways:

  • NF-κB Pathway: Central to the inflammatory response.
  • MAPK Pathway: Involved in cell survival and proliferation.
  • Apoptosis Pathway: Mediates cell death in response to TNF signaling.

8. Associated Genes:

  • TNF: The gene encoding TNF-alpha.
  • TNFRSF1A: The gene encoding TNF receptor 1.
  • TNFRSF1B: The gene encoding TNF receptor 2.
  • NFKB1: The gene encoding a key component of the NF-κB signaling pathway.

9. Target Expression:

TNF and its receptors are expressed in various tissues, including the immune system, synovial tissue, and inflamed tissues. Elevated levels of TNF are often found in the serum and synovial fluid of patients with autoimmune diseases (Balkwill, 2009).

10. Additional Context:

The development of TNF inhibitors has revolutionized the treatment of autoimmune diseases, providing effective options for patients who do not respond to traditional therapies. However, the use of these agents is associated with potential risks, including infections and malignancies, necessitating careful patient selection and monitoring (StatPearls, 2025).

11. References:

  • Tracey, D., Klareskog, L., & Sasso, E. H. (2008). Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacology & Therapeutics, 18155297.
  • Gerriets, V., Goyal, A., & Khaddour, K. (2025). Tumor Necrosis Factor Inhibitors. No journal info.
  • Mitoma, H., Horiuchi, T., & Tsukamoto, H. (2018). Molecular mechanisms of action of anti-TNF-alpha agents - Comparison among therapeutic TNF-alpha antagonists. Cytokine, 27567553.
  • Olesen, C. M., Coskun, M., & Peyrin-Biroulet, L. (2016). Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacology & Therapeutics, 26808166.
  • ACR Guidelines. (2021). 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.
  • StatPearls. (2025). Tumor Necrosis Factor Inhibitors - StatPearls - NCBI Bookshelf.
  • Balkwill, F. (2009). Tumour necrosis factor and cancer. Nature Reviews Cancer, 19343034.
  • Goldburg, S. R., Strober, B. E., & Payette, M. J. (2020). Hidradenitis suppurativa: Current and emerging treatments. Journal of the American Academy of Dermatology, 31604100.
  • Liu, T. W., Chen, C. M., & Chang, K. H. (2022). Biomarker of Neuroinflammation in Parkinson's Disease. International Journal of Molecular Sciences, 35456966.