Cytokines are proteins that are involved in cell signalling by binding to membrane-bound receptors. There are numerous families of cytokines, each with their own set of functions.
Chemokines
Chemokines are cytokines that induce chemotaxis of leukocytes primarily. They may also activate endothelial and epithelial chemotaxis in wound healing and morphogenesis. They are generally classified into four categories, based on their structure:
- CC chemokines induce migration of monocytes, NK cells and dendritic cells. Examples include monocyte chemoattractant protein-1, responsible for monocyte migration into tissue, and RANTES, which attracts T cells, eosinophils and basophils.
- CXC chemokines induce migration of neutrophils and lymphocytes. The best example is IL-8, which is chemotactic for neutrophils.
- C chemokines which increase intracellular calcium in lymphocytes and induces chemotaxis. There only two molecules in this category, both called lymphotactin.
- CX3C chemokines which only has one member, fractalkine. Fractalkine acts as a chemoattractant and adhesion molecule.
Chemokines bind to G-protein coupled receptors specific for their structural type. After binding, phospholipase C is activated, which cleaves PIP2 into DAG and IP3. IP3 triggers release of calcium from intracellular stores to activate the cell. Calcium and DAG combine to activate protein kinases that activate cells to degranulate, express integrins and undergo chemotaxis.
Colony-stimulating factors
There are two main colony-stimulating factors: granulocyte-macrophage CSF and granulocyte CSF. GM-CSF is a protein produced by leukocytes, endothelial cells and fibroblasts, and induces production of macrophages, neutrophils and eosinophils. G-CSF is specific for neutrophil proliferation, and is produced by endothelium and immune cells. These factors bind to precursors and stem cells in the bone marrow, and activate proliferation primarily through JAK/STAT pathways.
High Mobility Group Box Protein 1
HMGB-1 is a proinflammatory cytokine produced by macrophages. Its main role is binding DNA to regulate chromosome architecture and gene expression. Macrophages secrete the protein after identifying necrosis, allowing it to act as an alarmin. HMGB-1 binds to macrophage receptor for advanced glycosylation end products (RAGE) and TLRs 2 and 4. By completing this binding, it induces release of IL-1, TNF-α and IFN-ɣ, stimulating an immune response.
Interferons
Interferons are a group of cytokines produced primarily by lymphocytes, in response to viruses, parasites and neoplasia. There are three classes of interferons:
- Type I. The main Type I interferons are IFN-α and IFN-β. Generally, these interferons are produced in response to viral infections by fibroblasts and monocytes. They bind to IFN-α/β receptor (IFNAR), which signals through JAK/STAT. STAT1 and STAT2 combine with IRF3 to produce the IFN-stimulated gene factor 3 (ISGF3). ISGF3 acts as a transcription factor for expression of proteins used to prevent viral production and replication of RNA and DNA. Type I interferon production is inhibited by IL-10.
- Type II. The main Type II interferon is IFN-ɣ, which is activated by IL-12 and is only produced by immune cells. IFN-ɣ binds to IFN-ɣ receptor (IFNGR) which signals through JAK/STAT to produce Th1 and Th17 responses and block Th2 responses.
- Type III. This group includes IFN-λ, and are primarily produced by respiratory and intestinal cells after viral infection. They bind to unique receptors, including IL-10 receptors, and produce a response similar to Type II interferons.
Production of Type I interferons results in activation of several proteins that have antiviral activity. This activation is mediated by the ISGylation pathway, where ISG15 binds to several antiviral proteins and prevents their degradation. These proteins are:
- MxA, which binds and traps viruses.
- OAS1/RNase L, which cleaves viral RNA.
- PKR which inhibits host cell translation initiation factor-2α, preventing viral replication.
Interferons can also prevent viral spread by inhibiting p53, and may contribute to interferon’s protective role against cancer. They also enhance the presentation of viral antigens on MHCI (Type I interferons) and MHCII (Type II interferons), allowing for activation of an immune response against the virus.
Interleukins
Interleukins are a group of cytokines that activate leukocytes, primarily T and B lymphocytes. Most interleukins are produced by CD4+ helper T lymphocytes, but they can also be produced by macrophages and endothelial cells. The major interleukins and their functions are summarized below:
| Interleukin | Source | Notable Functions |
|---|---|---|
| IL-1 | Macrophages B cells Dendritic cells | Induces fever and acute phase reactions Activates T cells, B cells, NK cells and macrophages Inflammation |
| IL-2 | Th1 T cells | T cell growth and differentiation |
| IL-3 | CD4+ T cells Mast cells NK cells Endothelium Eosinophils | Proliferation of eosinophils Activation of mast cells |
| IL-4 | Th2 cells CD4+ T cells Macrophages Mast cells | IgE class switching and B cell proliferation T cell proliferation Expression of adhesion molecules on endothelium |
| IL-5 | Th2 cells Mast cells Eosinophils | Production of eosinophils IgA production by B cells |
| IL-6 | Macrophages Th2 cells Endothelium | T and B cell activation and differentiation Inflammation and acute phase reactions |
| IL-8 | Macrophages Lymphocytes Epithelial and endothelial cells | Neutrophil chemotaxis |
| IL-10 | Monocytes Th2 cells CD8+ T cells Mast cells | Cytokine production by macrophages Inhibits Th1 cytokine production Stimulation of Th2 cells |
| IL-12 | Dendritic cells B and T cells Macrophages | IFN-ɣ and TNF-α release, decreased IL-10 Cytotoxic T cell differentiation |
| IL-13 | Th2 cells Mast cells NK cells | Growth and differentiation of B cells Th1 cell inhibition Macrophage release of cytokines |
| IL-15 | Macrophages | Production of natural killer cells |
| IL-17 | Th17 cells | Angiogenesis Production of inflammatory cytokines |
| IL-18 | Macrophages | Production of IFN-ɣ Activation of NK cells |
| IL-23 | Macrophages Dendritic cells | Maintenance of IL-17 producing cells |
Tumor Necrosis Factors
Tumor necrosis factors are transmembrane proteins that can be released from the cell membrane by proteolysis, allowing them to function as a cytokine. They are primarily expressed by immune cells, and regulate immune responses and inflammation. The major TNFs are summarized below:
| Name | Function |
|---|---|
| Tumor necrosis factor (TNFα) | Induction of fever and cachexia Inflammation and apoptosis Sepsis |
| CD40 ligand | Activating antigen-presenting cells |
| Fas ligand | Inducing apoptosis in T cells |
| CD27 ligand | Regulation of B cell activation |
Transforming Growth Factor-Beta
TGF-β is a large family of proteins, composed of TGF-β, bone morphogenic protein, activin and inhibin. They interact with serine/threonine kinase receptors, leading to activation of a signalling pathway involving SMADs. Their main role is regulating growth, tissue homeostasis and immune system regulation.
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