Cytokines

Cytokines (literally “cell movement”) are a group of small proteins used in cell–signalling. They are produced by a wide range of cells, including macrophages, lymphocytes, mast cells, endothelial cells and fibroblasts. They are responsible for producing some of the cardinal signs of inflammation and influence both the innate and adaptive immune responses. There are different types of cytokines including chemokines, interferons, interleukins, lymphokines and tumour necrosis factors.

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

Chemokines

Chemokines induce chemotaxis (chemical-induced migration) in local cells. Following the 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 attracted are most needed. They are mainly produced by macrophages during infection, for example, Interleukin-8 (IL-8) recruits neutrophils to the site during the acute phase response.

Cells need chemokine receptors to respond to these cytokines. Chemokine receptors are G protein-coupled receptors which activate phospholipase C, leading to the release of calcium from intracellular stores. This, subsequently, gives rise to several downstream effects including, cytoskeletal changes, pseudopod formation and enhanced cell adhesion through integrins.

Chemokine Actions

Chemokines can have many actions within tissues. These can be:

• Pro-inflammatory – for instance, recruiting immune cells to the site of infection or injury.
  • These chemokines are inducible. Cells produce or upregulate pro-inflammatory chemokines in response to infection or trauma. Chemokine secretion is stimulated by other pro-inflammatory cytokines (TNF α, IFN γ) or microbial products (lipopolysaccharide). Pro-inflammatory chemokines allow immune cells such as neutrophils and monocytes to exit the bone marrow and hone into affected tissues.
• Homeostatic – for instance, attracting cells required for angiogenesis and allowing for the growth of new blood vessels.
  • These chemokines are constitutively produced. In other words, the body maintains basal levels without the need for a specific stimulus. For example, stromal cells within the bone marrow secrete CXCL12 which binds to its receptor, CXCR4, and this helps to retain neutrophils in the bone marrow until they are mobilised into the circulation during infection.
  • Chemokines are involved in immune surveillance and allow T cells and dendritic cells to migrate and circulate through secondary lymphoid organs in search of potential pathogens.
  • Chemokines are also key to the development of lymph organs and positioning of cells within lymphoid tissues. for example, a specific subset of B cells- responsible for mounting T-independent responses and producing IgM against encapsulated bacteria – localise to the marginal zone in the spleen through CXCR7.
• Note: some chemokines have both pro-inflammatory and homeostatic roles.

Pen1234567. Derivative of image by Kohidai, L. / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0)

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

Interferons are a type of cytokine released by host cells in response to pathogens (e.g. viruses and bacteria) and tumour cells. They are grouped according to their complementary receptor. There are three main groups: type I (interferon-α and interferon-β); type II (interferon-γ) and type III (Interferon λ). Type III has similar actions to type I and type II.

Interferon actions

These cytokines have a number of roles :

• Type-I Interferons
  • Almost any body cell can produce type-I interferons, including fibroblasts, endothelial cells and macrophages. Type I interferons such as Interferon-α and interferon-β interfere with viral replication and help the immune system fight viral infections. They are expressed in response to microbial products. Once secreted by the infected cell, they bind to the interferon receptors on the same cell and neighbouring cells. This autocrine and paracrine signalling causes changes in gene expression within the cell. As a result, this leads to the destruction of viral mRNA and prevents host and viral protein translation. They also upregulate NK cell ligands and MHC I on the cell surface. Therefore, NK cells and cytotoxic T cells are more likely to detect and attack virus-infected cells.
• Type-II interferons
  • Interferon-γ is a type-II interferon. NK cells, cytotoxic T cells and Th1 cells produce interferon-γ in response to IL-12 and IL-18. Interferon-γ activates macrophages and increases their ability to kill pathogens by enhancing pinocytosis and lysosome function. Type-II interferons also upregulate MHC II expression. This promotes antigen presentation and effective phagocytosis.
  • Note: there is overlap between interferon-I and interferon-II actions but they are both important for anti-viral and anti-tumour responses. 

Interleukins

Interleukins are another type of cytokine produced by T-lymphocytes, monocytes and macrophages. They have a wide range of functions, including:

• Promoting the production and differentiation of B and T lymphocytes – Specifically, IL-1α/β, IL-4, IL-7 and IL-21.
• Activating neutrophils and natural killer cells – for example, IL-2, IL-8 and IL-12.
• Producing detectable signs – interleukin-6 (IL-6) increases body temperature (fever) which inhibits microbial growth. IL-6, additionally, raises acute phase proteins such as C-reactive protein (CRP) which is associated with inflammation.
• Promoting vascular permeability which causes swelling and allows faster recruitment of cells involved in immunity.

Tumour Necrosis Factor

Tumour necrosis factor (TNF) is a cytokine 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 have similar functions, including:

• Local induction of apoptosis.
• Increasing local vascular permeability.
• Neutrophil chemotaxis.
• Stimulation of a pro-inflammatory state – for instance, by increasing CRP production in the liver and prostaglandin E2 production by macrophages. TNF also induces fever.
• Suppression of appetite.

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

Important Cytokines and Their Roles