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Original Author(s): Will Woodward
Last updated: 5th May 2020
Revisions: 4

Original Author(s): Will Woodward
Last updated: 5th May 2020
Revisions: 4

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Cytokines (literally “cell movement”) are a group of small proteins used in cell signalling. They are produced by a wide range of cells, such as macrophages, lymphocytes, mast cells, endothelial cells and fibroblasts and they are responsible for producing some of the cardinal signs of inflammation. As there are many types of cytokines they have been placed into different classes including chemokines, interferons, interleukins, lymphokines and tumour necrosis factors.

In this article we will look at different classes of cytokines and their actions.

Chemokines

These cytokines induce directed chemotaxis (chemical-induced migration) in local cells. That is, on release of chemokines, local cells are attracted to these proteins and follow their concentration gradient to the source, where the concentration is highest. The source is where the chemokines were originally released and where the cells that are attracted are most needed. They are mainly produced by macrophages during infection, for example IL-8, which attracts neutrophils to the site during the acute phase response.

Chemokines can have a variety of actions in a tissue such as:

  • Pro-inflammatory – recruiting immune cells to the site of infection or trauma
  • Normal cell migration – for example to attract cells required for angiogenesis to allow the growth of new blood vessels

Fig 1 – Diagram demonstrating the process of chemotaxis. The cell moves along the concentration gradient of chemokine to reach the area of highest concentration.

Interferons

These cytokines are released by host cells in response to pathogens (e.g. viruses and bacteria) and tumour cells.

Interferons have a number of roles, including:

  • Interfere (hence their name) with viral replication to help the immune system to fight viral infections – for example, interferon-α and interferon-β
  • Activate macrophages – for example, interferon-γ
  • Increase MHC expression

Interleukins

These cytokines are produced by T leucocytes, monocytes and macrophages of the innate immune system. They have a wide range of functions, including:

  • Promote the production and differentiation of B and T lymphocytes – for example, IL-1α/β, IL-4, IL-7 and IL-21
  • Activation of neutrophils and natural killer cells – for example, IL-2, IL-8 and IL-12
  • Produce detectable signs – interleukin-6 (IL-6) causes the elevated temperature (fever) which inhibits microbial growth and raises the acute phase proteins CRP which is associated with inflammation
  • Promote vascular permeability, allowing faster recruitment of cells involved in immunity and causing swelling

Tumour Necrosis Factor

Tumour necrosis factor (TNF) is mainly produced by macrophages when they encounter an endotoxin, however it can also be produced by other cells of the immune system including; mast cells; B cells and T cells. TNF α and β both have similar functions, including:

  • Local induction of apoptosis
  • Locally increased vascular permeability
  • Chemotaxis of neutrophils
  • Stimulation of a pro-inflammatory state – increased CRP production in the liver, increased production of prostaglandin E2 by macrophages and fever
  • Suppression of appetite

High concentrations of TNF can induce shock through the increase in vascular permeability and resulting drop in blood pressure. Chronic exposure to low levels on the other hand leads to the syndrome of cachexia often seen in chronic infection and cancer.

Important Cytokines and Their Roles

Cytokine Main Source Main Actions
IL-1 α/ β Macrophages ·         Fever

·         T-cell activation

·         Macrophage activation

IL-2 T helper 1 cells ·         Growth of T cells

·         Growth of B cells

·         Growth of NK cells

IL-4 T helper 2 cells ·         Activation and growth of B cells

·         Induces differentiation of CD4 T cells into T helper 2 cells

IL-6 Macrophages ·         Fever

·         Production of acute phase proteins

·         Lymphocyte activation

·         Stimulates antibody production

IL-8 Macrophages ·         Chemotaxis of neutrophils

·         Activation of neutrophils

IL-10 T helper 2 cells

Macrophages

·         Inhibits immune function
IL-12 Macrophages ·         Activation of NK cells

·         Induces differentiation of CD4 T cells into T helper 1 cells

IL-17 T helper 17 cells ·         Induces inflammatory response

·         Recruits neutrophils

Interferon-α T cells

B cells

Monocytes/Macrophages

·         Inhibits viral replication
Interferon-β T cells

B cells

Monocytes/Macrophages

·         Inhibits viral replication
Interferon-γ T helper 1 cells

NK cells

·         Activation of macrophages

·         Activation of NK cells

·         Inhibits viral replication

·         Increases expression of MHC class I and II

·         Inhibits T helper 2 cells

TNF-α/β T helper cells

Macrophages

·         Activation of macrophages

·         Nitric oxide production

·         Induces inflammatory response

·         Fever

·         Shock

Clinical Relevance – Cytokine Therapy

Because of their role in promoting and modifying immune responses, cytokines have been administered therapeutically in some conditions.

Interferons:

  • Hepatitis B and C to reduce risk of hepatocellular carcinoma
  • Chronic granulomatous disease to reduce risk of serious infection
  • Hairy cell leukaemia
  • Ovarian tumours

Interleukins:

  • Renal carcinoma
  • Melanoma

TNF:

  • Ovarian tumours