This is interleukin-1 (IL-1)
A potent pro-inflammatory cytokine
IL-1 is a potent pro-inflammatory cytokine that was first discovered as a fever- inducing molecule in 1974. It is produced during innate immune responses to infections and injuries. IL-1 drives inflammation by recruiting and activating immune cells, and inducing the production of various inflammatory mediators, including itself in a self-amplifying autoinflammatory loop.1-4
There are two different IL-1 proteins, IL-1α and IL-1β: IL-1α is an alarmin that is found in many different cell types and is released during cell death, ‘alarming’ the immune system to the presence of danger and triggering local (sterile) inflammation; by contrast, IL-1β is mainly produced by activated innate immune cells such as monocytes, macrophages, and neutrophils. IL-1α and IL-1β bind to the same receptor, IL-1R1, and induce the same pro-inflammatory effects.1-4
While IL-1 plays an important role in protective immune responses, abnormal or inadequately regulated IL-1 signaling may lead to excessive inflammation and tissue damage. Given the potent pro-inflammatory effects of IL-1, physiological negative regulators exist, for example the naturally-occurring IL-1 receptor antagonist that blocks IL-1 from binding to IL-1R1. However, if too much IL-1 is produced and/or regulating mechanisms are insufficient, IL-1-driven inflammation may have harmful consequences and contribute to the pathogenesis of inflammatory conditions.1-4
The Story of IL‑1, full length
This is the story of Interleukin 1. A defense mechanism that is present in all humans and that is essential for our survival. But how did it all start?
In this video Professor Charles A. Dinarello and Peter Brodin explain the discovery and functions of Interleukin 1 (IL-1).
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Signs and symptoms of IL-1-mediated inflammation
Typical signs and symptoms of IL-1-mediated inflammation include fever, eleva- tion of acute phase reactants (e.g. C-reactive protein, serum amyloid A), neutrop- hilia, and tissue inflammation commonly affecting the skin and musculoskeletal system, but various other organs may also be affected.1
The effects of unopposed, excessive IL-1 signaling are exemplified by the syste- mic, potentially life-threatening, sterile inflammation seen in patients with defi- ciency of IL-1 receptor antagonist (DIRA), who present with neutrophilia, elevated inflammatory markers, and inflammation of the skin, joints, and bones.1-4
In patients with the monogenic periodic fever syndromes cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF), abnormal, increased production of IL-1 due gain-of-function mutations in the NLRP3 and pyrin inflammasomes lead to recurrent fever episodes, elevation of acute phase reactants, and various inflammatory manifestations involving e.g. the joints (arthritis/arthralgia), skin (rash), eyes (conjunctivitis), serosal membranes (perito- neum, pleura, leading to abdominal and chest pain), and other organs.1-3
IL-1-driven inflammation also plays an important role in Still’s disease, which is characterized by spiking fever, rash, and joint involvement (arthralgia and/or arthritis), as well as neutrophilia and elevated CRP and ferritin.1-3
In patients with rheumatoid arthritis, IL-1 contributes to joint inflammation and tissue damage by stimulating the production of pro-inflammatory mediators and cartilage-degrading enzymes, and activating bone-resorbing osteoclasts.2,3
IL-1 has also been implicated in the hyperinflammatory response observed in se- vere cases of COVID-19. Blocking IL-1 activity has been shown to mitigate the risk of developing severe respiratory failure in COVID-19 patients hospitalised with pneumonia and plasma suPAR ≥6 ng/ml.4-7
Abbreviations
IL-1, interleukin-1; IL-1R1, Interleukin-1 receptor type 1; CRP, C-reactive protein; NLRP3, NOD-like receptor family pyrin domain-containing 3.
Kineret Q&A
- Kineret is given in a pre-filled syringe containing 100 mg of anakinra per 0.67 ml (150 mg/ml).1
- Kineret is given as a subcutaneous injection.1
- Dosage depends on indication. In children, the dose is determined depending on body weight. Please refer to current SmPC.
- Kineret should be stored in a refrigerator between 2°C and 8°C.1
- Kineret should not be frozen or shaken.1
- Kineret should be kept in its original carton and away from light.1
References
- Broderick L and Hoffman HM. IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting. Nat Rev Rheumatol 2022;18(8):448–463.
- Schett G, Dayer J-M, and Manger B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol 2016; 12 (1): 14–24.
- Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52.
- Cavalli G, Colafrancesco S, Emmi G, Imazio M, Lopalco G, Maggio MC, et al. Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases. Autoimmun Rev. 2021;20(3):102763.
- van de Veerdonk, F.L., Netea, M.G. Blocking IL-1 to prevent respiratory failure in COVID-19. Crit Care 24, 445 (2020).
- Kyriazopoulou E, Panagopoulos P, Metallidis S, Dalekos GN, Poulakou G, Gatselis N, et al. An open label trial of anakinra to prevent respiratory failure in COVID-19. Elife. 2021 Mar;10:e66125–e66125.
- Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, Adamis G, Tsiakos K, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. NatMed. 2021;27(10):1752-1760.
- Swedish Orphan Biovitrum AB (publ). Kineret summary of product characteristics [SmPC]. Latest version available from: https:// www.ema.europa.eu/en/documents/product-information/kineret-epar-product-information_en.pdf