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Cytokines

The immune system is a complex but coordinated system of cells, tissues, and soluble molecules that constitute the body's defence against invasion by non-self entities, including infectious and inert agents and tumour cells.

Immune homeostasis is the delicate balance of all immune responses used to fight disease.1 Immune homeostasis is affected by a number of different factors, both inherited and acquired:

Immune homeostasis naturally fluctuates over time, but in some cases the balance of pro-inflammatory and anti-inflammatory responses can shift to a new equilibrium, leading to diseases characterised by chronic immunosuppression or chronic inflammation.1

  • Chronic immunosuppression: too little inflammation may allow uncontrolled growth of pathogens or cancer cells
  • Chronic inflammation: too much inflammation may cause a variety of autoimmune conditions affecting one or several organ systems

Cytokines regulate many biological processes

Cytokines (greek, cyto- ‘cell’ & kinos – ‘movement’) are small molecules that mediate communication between cells resulting in:2

  • attraction of inflammatory and immune cells to a site within the body
  • activation of cells to release products that lead to tissue destruction

Cytokines may be classified according to function;2 however, the definition of cytokine function is ever-changing, with many cytokines playing multiple roles and falling into more than one category:

  • Inflammatory Response: The traditional paradigm of ‘pro-inflammatory’ and ‘anti-inflammatory’ cytokines has been challenged in recent years, and it should be noted that individual cytokines can exert diverse and even opposing effects, depending on the environment in which they are acting.3 Cytokines that are commonly seen as ‘pro-inflammatory’ cytokines include the TNF superfamily and IL-1 superfamily,3 amongst others. Examples of ‘anti-inflammatory’ cytokines include IL-4, IL-10, IL-13, IFN-α and TGF-β. Furthermore, specific cytokine receptors for IL-1, TNFα, and IL-18 also function as pro-inflammatory cytokine inhibitors.4
  • Chemotaxis: Chemotactic cytokines (‘chemokines’) stimulate the migration and activation of cells, especially phagocytic cells and lymphocytes. In the inflammatory response, they regulate the chemotaxis (movement in response to chemicals) of leucocytes, generally by attracting them to the site of inflammation.2 
  • Haematopoiesis: Haematopoietic cytokines are those known to be related to the formation of blood cells4; e.g. erythropoietin, G-CSF and GM-CSF.5
  • Growth and differentiation: Some cytokines are growth factors (e.g. G-CSF and GM-CSF), which promote growth and development by directing cell maturation and differentiation and by mediating maintenance and repair of tissues.4

Cytokines drive the inflammatory response in autoimmune diseases

In immune homeostasis, a complex network of cytokines balances pro-inflammatory and anti-inflammatory effects.6,7 Autoimmune diseases are, broadly speaking, the result of an imbalance between pro- and anti-inflammatory cytokines. In chronic autoimmune diseases, for example rheumatoid arthritis, joint destruction is driven by cytokine release.

* IL-1Rα , IL-18BP , IL-10 , TGF-β , IL-11 , IL-13.
** TNF , LT , IL-1β , IL-6 , IL-7 , IL-8 , IL-12, IL-17, IL-18 , IL-23 , IFN

TNF-tumour necrosis factor; IL-interleukin; IFN-interferon; TGF-B- transforming growth factor-beta; G-CSF-Granulocyte-colony stimulating factor; GM-CSF-Granulocyte/Macrophage-colony stimulating factor; LT-Leukotrienes; IL-18BP-interleukin-18 binding protein; Th-T-helper cell; T reg-T-regulatory cell.

Cytokine loops: Perpetuating the inflammatory signal

The chronic inflammatory state in autoimmune diseases occurs as a result of a continuing pro-inflammatory ‘cytokine loops’ whereby cytokines attract and stimulate immune cells to release more cytokines, which further stimulate production of cytokines. This process can lead to perpetuation or amplification of the inflammatory state.7


Prescribing Information:
​​​​​​​

Xeljanz (tofacitinib citrate) Prescribing Information (Great Britain) - 5mg film-coated tablets
Xeljanz (tofacitinib citrate) Prescribing Information (Great Britain) - 10mg film-coated tablets
Xeljanz (tofacitinib citrate) Prescribing Information (Northern Ireland) -  5mg and 10mg film-coated tablets
​​​​​​​Xeljanz (tofacitinib citrate) Prescribing Information (Great Britain) -  11mg prolonged release tablets
Xeljanz (tofacitinib citrate) Prescribing Information (Northern Ireland) -  11mg prolonged release tablets


​​​​​​​References:
  1. Crimeen-Irwin B, et al. Failure of immune homeostasis -- the consequences of under and over reactivity. Curr Drug Targets Immune Endocr Metabol Disord 2005;5(4):413-422.
  2. Murphy K, Weaver C. Janeway’s Immunobiology. 9th ed. New York, NY: Garland Science, Taylor & Francis Group, LLC; 2016.
  3. Muzes G et al. Changes of the cytokine profile in inflammatory bowel disease. World J Gastroenterol 2012:18(41):5848-5861
  4. Opal SM & DePalo VA. Anti-inflammatory cytokines. Chest 2000;117(4):1162-1172.
  5. Metcalf D. Hematopoietic cytokines. Blood. 2008: 11(2):485-491.
  6. Chizzolini C, et al. Cytokines in chronic rheumatic diseases: is everything lack of homeostatic balance? Arthritis Res Ther 2009; 11(5): 246-256.
  7. McInnes IB, Liew FY. Cytokine networks-towards new therapies for rheumatoid arthritis. Nat Clin Pract Rheumatol 2005; 1(1): 31-39.
PP-XEL-GBR-3124. August 2021

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XELJANZ Risk Minimisation Programme (RMP) materials, including a Patient Alert Card, Prescriber Checklists and a Prescriber Brochure are available from https://www.medicines.org.uk/emc/. Patients treated with XELJANZ should be given the Patient Alert Card.

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