An Overview of Cytokine Regulation of Inflammation and Immunity

Abstract

The defence of an organism depends on the recognition of harmful stimuli followed by appropriate activation of innate and adaptive immune responses. Primary recognition of harmful stimuli is mediated by specific receptors of monocytes, macrophages and dendritic cells, leading to cytokine production. Several cytokines have proinflammatory actions that drive the innate immune response, cause inflammation and activate adaptive immune responses. Further activation of adaptive immunity depends on cytokine regulation of T‐cell differentiation into specific T‐cell subsets with specific roles in defence against the invading pathogens. Although cytokine regulation of inflammation and immunity is crucial for protection against infection and injury, their actions in excess are associated with a variety of autoinflammatory and autoimmune diseases.

Key Concepts:

  • Cytokines are a broad class of biologically active proteins with hormone‐like actions that are produced in response to homoeostatic, and more particularly harmful, stimuli.

  • The extent of cytokine production is dependent both on the nature of the stimulus and on regulatory intracellular mechanisms.

  • Cytokines may act on any cells that bear receptors, by which, with the involvement of signal transduction pathways, nuclear gene transcription is activated.

  • Many cytokines act on cells of the immune and vascular systems to regulate cell proliferation, differentiation and activation of pro‐ or anti‐inflammatory mechanisms.

  • Monocytes, macrophages and dendritic cells bear ‘pattern recognition receptors’ and are especially sensitive to harmful stimuli such as pathogens bearing ‘pathogen‐associated molecular patterns (PAMPs)’.

  • Monocytes and macrophages produce the proinflammatory cytokines, for example, interleukin‐1, tumour necrosis factor‐α, responsible for inflammatory reactions and innate immune responses.

  • Cytokines such as interleukin‐12, interleukin‐18 and interleukin‐23 couple the innate immune response to adaptive immune responses mediated by T cells, B cells and natural killer cells.

  • T‐cell differentiation into specific T‐cell subsets is governed by several cytokines, for example, interleukin‐4 and interferon‐gamma, acting antagonistically to one another.

  • Excessive cytokine production or action leads to acute or chronic inflammation, which may trigger autoinflammatory and autoimmune diseases in the long term.

Keywords: cytokine; interleukin; inflammation; immunity; monocyte; macrophage; T cell; natural killer cell

Figure 1.

Schematic diagram illustrating the proposed interactions of pro‐ (black) and anti‐ (red) inflammatory interleukins and other cytokines in the mediation of acute and chronic inflammation. The chemokine IL‐8 released from macrophages and APCs forms a chemotactic gradient to attract neutrophils (N) to sites of injury and infection. The expression of cellular adhesion molecules, for example, intercellular adhesion molecule‐1 (ICAM‐1), is markedly increased by IL‐1β, IL‐17A and TNFα leading to neutrophil adherence to the endothelial cells lining the blood capillaries, following which N transmigrate into the injured/infected tissue. Neutrophils and T‐cell infiltrates (not shown) release more proinflammatory ILs and cytokines to resolve the injury/infection, but which may lead, if not appropriately regulated, to aggressive T cell‐mediated attack on host tissues and ultimately to profound autoimmune disease. TRegs act to dampen excessive immune attack by releasing IL‐10 and TGF‐β1, which inhibit TH17 cell activation.

Figure 2.

Schematic diagram of the proposed cytokine‐regulated pathways for the differentiation and development of functional T‐cell subsets. Each TH subset expresses a unique ‘portfolio’ of ILs and other cytokines that pertains to their function: TH1 subset upregulates cell‐mediated immunity; TH2 subset provides ‘help’ for humoral immune responses, including immunoglobulin production from B cells and mast cells; TH17 subset probably provides ‘early’ defence against large injuries and infections. CD8+ T cells form the majority of CTL, which attack and kill foreign antigen‐presenting cells. Once the injury/infection is resolved, the functional responsiveness of T cells is shutdown by IL‐10 and TGFβ1 secreted by TReg. Memory T cells then may develop, which are sustained by IL‐7.

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Meager, Anthony, and Wadhwa, Meenu(Sep 2013) An Overview of Cytokine Regulation of Inflammation and Immunity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024658]