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Iain B. McInnes

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date: 27 March 2017

Cytokines are small glycoprotein mediators that are involved in every facet of immune effector function and regulation. More than 200 cytokines have been identified, which may usefully be classified in structurally related superfamilies. They can (1) function through binding to specific receptors that in turn signal via complex transduction pathways to regulate gene expression, thereby mediating positive and negative regulatory activities; (2) operate as soluble mediators in the extracellular domain or within cells, where they may also traffic to the nucleus and exhibit dual function as transcriptional regulators; (3) be expressed initially on the cell membrane, where they may exert effector function directly in cell–cell interactions, or from which they can be subsequently cleaved to yield bioactive soluble molecules, thereby mediating autocrine and paracrine activities around their cellular source.

The innate immune response—this is designed to offer immediate effector defence and comprises particular leucocyte lineages including neutrophils, eosinophils, monocytes/macrophages and natural killer cells. It is regulated by cytokines such as the type I interferons (IFN), tumour necrosis factor (TNF) α‎, and interleukin (IL) IL-1α‎, IL-6, IL-15, and IL-18. These are produced rapidly in large amounts, work along with pattern-recognition receptor families such as Toll-like receptors to coordinate local cellular activation, and are essential for the integrity of the innate immune response. Over time, additional cytokines such as IL-10 and tissue growth factor (TGF) β‎ are synthesized, promoting resolution of immune responses and mediating healing of tissue damage. However, such responses are amnesic in that no specific molecular memory of the initiating stimulus is retained beyond pattern recognition.

Adaptive immune responses—these are an evolutionary refinement to facilitate recall responses to specific antigens derived from invading organisms or damaged self-tissue. Adaptive immunity to antigenic stimuli is initiated primarily via the activation of professional antigen-presenting cells, such as dendritic cells and macrophages, working in synergy with cytokines. Dendritic cells are activated by cytokines such as TNFα‎ and IL-1α‎ to increase antigen uptake, processing and presentation to naive T cells, and—critically—dendritic cells use cytokines to define the phenotype of subsequent T-cell responses: (1) production of IL-18 and IL-12 promotes a Th1 response (IFNγ‎ predominant); (2) production of IL-1, IL-6, IL-21, and IL-23 favours the emergence of a Th17 response (IL-17A, IL-17F, IL-22 predominant); and (3) production of IL-4 and IL-33 favours Th2 cell differentiation (IL-4, IL-5, IL-13 predominant). Regulatory T-cell subsets may also be activated in this phase by cytokines such as IL-2, IL-10, IL-35 and TGFβ‎.

Activation of host-tissue cell types—cytokines mediate many effector functions in the immune system by action on host-tissue cell types, including (1) activation of endothelial and lymphendothelial cells to express adhesion molecules and to alter their permeabililty properties to facilitate induction and resolution of inflammation; (2) regulation of differentiated tissue specific cells, which can contribute indirectly to host tissue defence; (3) regulation of host tissue function in the context of inflammation, e.g. by facilitating metabolic responses to sustain energy requirements for host defence responses.

Clinical context—cytokines play a broad role in numerous biological systems. This renders them of basic scientific interest. Understanding of the cytokine network also has increasing importance in clinical practice with the advent of therapeutic strategies that target particular cytokines with exquisite specificity using biological agents, leading to remarkable advances in the treatment of inflammatory disorders, e.g. anti-TNF therapy in rheumatoid arthritis.

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