Tumor Necrosis Factor (TNF)

Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor necrosis factor interacts with 2 receptors, which initiate signal transduction pathways leading to different cellular responses (inflammation, cell survival, or apoptosis). Inappropriate or unrestrained activation of TNF signaling produces chronic inflammation, as seen in autoimmune conditions (e.g., rheumatoid arthritis, psoriasis). The mechanism of TNF inhibition has been used in treating these inflammatory diseases.

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Overview

Tumor necrosis factor (TNF)

  • Other names: TNF-ɑ, cachectin
    • Originally, the protein derived from macrophages was named tumor necrosis factor and a second, related, one derived from lymphocytes was named lymphotoxin. 
    • Being bound to the same receptor and sharing similarities in amino acid sequences, these proteins were previously called:
      • TNF-α (for TNF)
      • TNF-β (for lymphotoxin)
    • Further studies on the protein sequences now identify multiple members (ligands and receptors) of the TNF superfamily.
  • Major cytokine, released primarily by macrophages in response to stimuli (such as lipopolysaccharides or other toll-like receptor-activating stimuli)
  • Other cells (e.g., T cells, mast cells, fibroblasts) also produce TNF.

General functions of tumor necrosis factor

  • Proinflammatory:
    • Endothelial activation:
      • ↑ Endothelial adhesion molecules (e.g., P-selectin, E-selectin)
      • ↑ Mediators (other cytokines, chemokines, eicosanoids)
      • ↑ Procoagulant activity
    • Activation of immune cells (such as leukocytes)
    • Acute-phase response: lipid and protein mobilization and ↓ appetite (leading to weight loss and cachexia)
  • Cell proliferation and differentiation
  • Apoptosis 
  • Antitumor activity

Tumor Necrosis Factor Superfamily

Members of the superfamily

  • 19 ligands interacting with 29 receptors; each ligand able to interact with > 1 receptor 
  • Proinflammatory properties are predominantly present in the ligands.
  • Most members have protective roles but also have harmful effects (with links to a variety of diseases).

Notable members

  • TNF: 
    • Fever (pyrogenic)
    • Antitumor
    • Mediator of inflammation and sepsis
  • Lymphotoxin:
    • Mediator of inflammation
    • Antiviral response
    • Antitumor
    • Control of secondary lymphoid organ development
  • CD40 ligand (CD40L): 
    • Expressed in T cells and interacts with the CD40 on B cells
    • ​​CD40L–CD40 induces B-cell proliferation, class-switch recombination, and somatic hypermutation.
  • Fas ligand (FasL):
    • Expressed in cytotoxic T cells
    • Interaction of FasL and Fas (a death receptor) → Fas-associated protein with death domain (FADD) → caspase 8 activation → apoptosis

Effects of Tumor Necrosis Factor

Induction

  • TNF produced by various cells (predominantly macrophages); stimuli include:
    • Microbial products (e.g., lipopolysaccharide)
    • Dead cells
    • Immune complexes
    • Foreign antigens/bodies
    • Physical injury
    • IL-1
  • Starts initially as membrane-bound (pro-TNF):
    • Then expressed as a transmembrane protein
    • Requires proteolytic cleavage by TNF-α–converting enzyme (TACE) → releasing the soluble form of TNF

Tumor necrosis factor receptors

  • The functions of TNF are mediated by 2 receptor types:
    • TNFR1: 
      • Extensively studied
      • More prevalent
      • Expressed universally on almost all cell types
      • Contains death domain (DD) and is a member of the death receptor family, with capacity to induce apoptotic death
    • TNFR2: 
      • Mainly restricted to immune cells and some tumor cells 
      • Does not have DD, but has TNF-receptor–associated factor (TRAF) binding site
      • Believed to have a role in cell survival and regeneration
  • Receptors trigger distinct, but also interconnected, signaling pathways.

Effects

  • TNF, via TNFR1:
    • Inflammatory effect: 
      • Certain proteins (TNF-receptor type 1–associated death domain (TRADD), TNF-receptor–associated factor 2 (TRAF2), and receptor interacting protein (RIP)) are sequentially recruited.
      • Proinflammatory pathways such as nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways are activated.
      • NF-κB activation → transcription of inflammatory proteins, cell survival and proliferation, induction of antiapoptotic genes
    • Apoptotic effect: 
      • TRADD and FADD are recruited.
      • Activation of caspase 8 is triggered → proteolytic cascade → apoptosis
  • TNF, via TNFR2:
    • TRAF2 is recruited → activation of different pathways, such as NF-κB and MAPK
    • Effects: 
      • Tissue/cell regeneration, proliferation, and survival
      • Host defense against pathogens (inflammation)
TNF-receptor-TNFR-pathway-of-signaling-Two-complex-model-is-shown-Upon-ligation-with tumor necrosis factor

Tumor necrosis factor (TNF) receptor (TNFR) pathway of signaling:
On the left (labeled as complex I), with ligation of TNF-α, TNFR recruits various adapter molecules, resulting in the activation of nuclear factor kappa-B (NF-κB), which induces several antiapoptotic genes and the survival signal. FLICE inhibitory protein (FLIP) and inhibitor of apoptosis proteins (IAPs) modulate and inhibit the apoptosis pathway.
On the right (labeled as complex II), TNFR without certain adapter proteins (TNF-receptor–associated factor 2 (TRAF2), receptor-interacting protein (RIP)) leads to recruitment of Fas–associated death domain (FADD).
Caspase 8 is activated and released into the cytoplasm, where it activates effector caspases to induce apoptosis.
IKK: IκB kinase

Image: “TNF receptor (TNFR) pathway of signaling” by Gupta S et al. License: CC BY 2.0

Tumor Necrosis Factor and Diseases

Diseases

  • Binding to 2 different receptors, TNF initiates signal transduction pathways that produce varying cellular responses, including cell survival, differentiation, proliferation, and cell death.
  • Inappropriate or unrestrained activation of TNF signaling produces chronic inflammation → pathologic complications such as autoimmune diseases 
  • Abnormal secretion of TNF has been associated with:
    • Rheumatoid arthritis
    • Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
    • Psoriatic arthritis
    • Psoriasis
    • Noninfectious uveitis

Anti–tumor necrosis factor therapy

Tumor necrosis factor has multiple biologic effects, and in certain conditions (e.g., rheumatoid arthritis), elevated levels of TNF have been noted. The mechanism of TNF inhibition has been used in treating inflammatory diseases.

Table: Indications for anti–tumor necrosis factor therapy
Anti-TNF therapyMechanism of actionIndications
InfliximabRecombinant chimeric antibody (having a murine variable region and a human IgG1 constant region) that binds to TNF, preventing receptor interaction
  • Crohn’s disease
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Plaque psoriasis
  • Psoriatic arthritis
  • Ulcerative colitis
EtarneceptFusion protein that binds and neutralizes TNF and lymphotoxin
  • Plaque psoriasis
  • Polyarticular juvenile idiopathic arthritis
  • Psoriatic arthritis
  • Rheumatoid arthritis
AdalimumabFully humanized IgG1 monoclonal antibody that blocks TNF binding to receptors
  • Ankylosing spondylitis
  • Crohn’s disease
  • Hidradenitis suppurativa
  • Juvenile idiopathic arthritis
  • Psoriatic arthritis
  • Rheumatoid arthritis
  • Ulcerative colitis
  • Uveitis
GolimumabFully humanized IgG1 monoclonal antibody with high affinity and specificity for TNF
  • Ankylosing spondylitis
  • Psoriatic arthritis
  • Rheumatoid arthritis
  • Ulcerative colitis
CertolizumabPegylated humanized monoclonal antibody specific to TNF
  • Ankylosing spondylitis
  • Crohn’s disease
  • Psoriatic arthritis
  • Plaque psoriasis
  • Rheumatoid arthritis

Clinical Relevance

  • Crohn’s disease (CD): chronic, recurrent condition that causes patchy transmural inflammation that can involve any part of the GI tract. The terminal ileum and proximal colon are usually affected. Crohn’s disease presents with intermittent, nonbloody diarrhea and crampy abdominal pain. Extraintestinal manifestations may include calcium oxalate renal stones, gallstones, erythema nodosum, and arthritis. Diagnosis is established via endoscopy with biopsy. Management is with corticosteroids, azathioprine, antibiotics, and anti-TNF agents (infliximab and adalimumab). 
  • Ulcerative colitis (UC): idiopathic inflammatory condition that involves the mucosal surface of the colon. The rectum is always involved in UC, and inflammation may extend proximally through the colon. Ulcerative colitis causes diffuse friability, erosions with bleeding, and loss of haustra, which are visible on endoscopy. Individuals present with bloody diarrhea, colicky abdominal pain, tenesmus, and fecal urgency. Diagnosis is established via endoscopy with biopsy. Management includes topical mesalamine, 6-mercaptopurine, and anti-TNF agents or colectomy for severe cases.
  • Psoriasis: common T-cell–mediated inflammatory skin condition. The etiology is unknown, but psoriasis is thought to be due to genetics and environmental triggers. Plaques are well circumscribed, are salmon-colored, and have silvery scales. The plaques commonly appear on the scalp and extensor surfaces of the extremities. The diagnosis is clinical. Treatment options include topical corticosteroids, retinoids, calcineurin inhibitors, disease-modifying antirheumatic drugs (DMARDs), biologics such as anti-TNF agents, and phototherapy. 
  • Ankylosing spondylitis: also known as Bechterew’s disease or Marie-Strümpell disease. Ankylosing spondylitis is a seronegative spondyloarthropathy characterized by chronic and indolent inflammation of the axial skeleton. Severe disease can lead to fusion and rigidity of the spine. The condition is most often seen in young men and is associated with HLA-B27. Individuals will have progressive back pain (which improves with activity), morning stiffness, and decreased range of motion of the spine. Extraarticular manifestations are also noted. Diagnosis is based on the clinical history, exam, and imaging (sacroiliitis and bridging syndesmophytes). Management involves physical therapy and NSAIDs. More severe cases may require TNF inhibitors or surgery.
  • Rheumatoid arthritis: symmetric, inflammatory polyarthritis. Rheumatoid arthritis is a chronic, progressive autoimmune disorder. Presentation includes joint swelling, pain, and morning stiffness (often in the hands). Prolonged and severe disease can lead to irreversible joint deformities. Systemic inflammation can lead to extraarticular manifestations, including rheumatoid nodules, interstitial lung disease, Felty syndrome, and pericarditis. Diagnosis is clinical and is confirmed by the presence of rheumatoid factor, anti–cyclic citrullinated peptide antibodies, and characteristic imaging findings. Management involves physical therapy, long-term DMARDs, and biologics such as anti-TNF agents. 
  • Hidradenitis suppurativa (HS): chronic skin condition due to the inflammation of apocrine sweat glands and hair follicles. Hidradenitis suppurativa commonly occurs because of occlusion of the follicular component of pilosebaceous units (PSUs). Hidradenitis suppurativa is characterized by the formation of abscesses, fistulas, draining skin lesions, keloids, and pilonidal sinuses. The diagnosis of HS is primarily clinical. Management includes lifestyle changes (weight loss and smoking cessation) and medical treatment with antibiotics, retinoids, and anti-TNF agents. Resistant disease requires surgery.

References

  1. Aggarwal, B.B. (2003). Signaling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756. 
  2. Aggarwal, B.B., Gupta, S.C., Kim, J.H. (2012). Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood 119:651–665. doi:10.1182/blood-2011-04-325225
  3. Beutler, B., Moresco, E.Y. (2021). Innate immunity. Chapter 19 of Kaushansky, K., Prchal, J.T., Burns, L.J., Lichtman, M.A., Levi, M., Linch, D.C. (Eds.),  Williams Hematology, 10th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2962&sectionid=252524927
  4. Burmester, G. (2021). Overview of biologic agents and kinase inhibitors in the rheumatic diseases. UpToDate. Retrieved Aug 7, 2021, from https://www.uptodate.com/contents/overview-of-biologic-agents-and-kinase-inhibitors-in-the-rheumatic-diseases
  5. Grimstad, Ø. (2016). Tumor necrosis factor and the tenacious α. JAMA Dermatol 152:557. https://pubmed.ncbi.nlm.nih.gov/27168212/
  6. Kalliolias, G.D., Ivashkiv, L.B. (2016). TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nature Reviews Rheumatology 12(1):49–62. https://doi.org/10.1038/nrrheum.2015.169
  7. Krensky, A.M., Azzi, J.R., Hafler, D.A. (2017). Immunosuppressants and tolerogens. Chapter 35 of Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172480027
  8. Kumar, V., Abbas, A. Aster, J. (2021). Inflammation and repair. In: Robbins and Cotran Pathologic Basis of Disease, 10th ed. Elsevier, pp. 88–90).
  9. Jang,D., Lee, A.-H., Shin, H.-Y.,  Song, H.-R., Park, J.-H., Kang, T.-B., Lee, S.-R., Yang, S.-H. (2021). The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. Int J Mol Sci 22:2719. https://pubmed.ncbi.nlm.nih.gov/33800290/
  10. Varfolomeev, E., Ashkenazi, A. (2004). Tumor necrosis factor. Cell 116:491–497. https://doi.org/10.1016/S0092-8674(04)00166-7
  11. Wang, X., Lin, Y. (2008). Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacologica Sinica 29:1275–1288. https://doi.org/10.1111/j.1745-7254.2008.00889.x

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