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MECHANISM OF AUTOINFLAMMATORY DISEASE

Proinflammatory Cytokines

Underlying Drivers of Autoinflammatory Disease1-4

Autoinflammatory diseases are driven by an excess of proinflammatory cytokines5-10

  • IL-1β is a key driver of autoinflammatory disease
  • IL-6, IL-18, and TNF also play a role in autoinflammatory diseases

Proinflammatory cytokines serve various functions in the body

  • It is released from the cell and elicits inflammatory responses, including triggering production of proinflammatory cytokines such as IL-6 and TNF, stimulating the production and release of the acute-phase proteins from the liver, acting on the hypothalamus to induce fever and pain sensitization, and acting on bone to induce bone resorption, cartilage breakdown, and production and enhanced activation of lymphocytes, neutrophils, and platelets4,11
  • IL-1β also acts via a positive feedback loop to induce even more IL-1β, further perpetuating inflammation
  • IL-6 is a reliable marker of inflammation
  • IL-18 is a pro-inflammatory cytokine found in the synovial fluid of joints in patients with Still’s disease
  • However, in TNF receptor–associated periodic syndrome (TRAPS), mutant TNF receptor 1 appears to have defects and is thought to bind TNF less effectively leading to cell death, prolonged immune response to non-mutated receptor bound TNF and uncontrolled downstream signaling6

Cytokines and their role in autoinflammatory disease4,8

The overproduction of these proinflammatory cytokines can trigger a range of responses, including:

  • Systemic inflammation
  • Fever
  • Pain
  • Bone and joint damage
  • Leukocyte activation

IL-1β is released from the cell and elicits inflammatory responses4,8,11

Inflammatory Responses
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The IL-1 pathway is critical in autoinflammatory disease activity4

Learn More
IL-1=interleukin 1; IL-1β=interleukin 1 beta; IL-6=interleukin 6; IL-18=interleukin 18; TNF=tumor necrosis factor.
References: 1. Lopez-Castejon G, Brough D. Understanding the mechanism of IL-1β secretion. Cytokine Growth Factor Rev. 2011;22(4):189-195. doi:10.1016/j.cytogfr.2011.10.001 2. Jain S, Gautam V, Naseem S. Acute-phase proteins: As diagnostic tool. J Pharm Bioall Sci. 2011;3(1):118-127. doi:10.4103/0975-7406.76489 3. Jesus AA, Goldbach-Mansky R. Annu Rev Med. 2014;65:223-244. doi:10.1146/annurev-med-061512-150641 4. Lachmann HJ, Quartier P, So A, Hawkins PN. The emerging role of interleukin-1β in autoinflammatory diseases. Arthritis Rheum. 2011;63(2):314-324. doi:10.1002/art.30105 5. McGeough MD, Pena CA, Mueller JL, et al. Cutting edge: IL-6 is a marker of inflammation with no direct role in inflammasome-mediated mouse models. J Immunol. 2012;189:2707-2711. doi:10.4049/jimmunol.1101737 6. Ostrov BE. Immunotherapeutic biologic agents to treat autoinflammatory diseases. In: Metodiev K, ed. Immunotherapy - Myths, Reality, Ideas, Future. InTech; 2017: chap 12. Accessed March 2, 2020. doi:10.5772/66547 7. Lopalco G, Cantarini L, Vitale A, et al. Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives. Mediators Inflamm. 2015;2015:194864. doi:10.1155/2015/194864 8. Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1β in inflammatory disorders. Nat Clin Pract Rheumatol. 2008;4(1):34-42. doi:10.1038/ncprheum0681 9. Lin Y-T, Wang C-T, Gershwin ME, Chiang B-L. The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev. 2011;10(8):482-489. doi:10.1016/j.autrev.2011.02.001 10. Mellins ED, Macaubas C, Grom AA. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol. 2011;7(7):416-426. doi:10.1038/nrrheum.2011.68 11. Jamilloux Y, Gerfaud-Valentin M, Martinon F, Belot A, Henry T, Sève P. Pathogenesis of adult-onset Still’s disease: new insights from the juvenile counterpart. Immunol Res. 2015;61(1-2):53-62. doi:10.1007/s12026-014-8561-9

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Last updated May 2021