Cytokines are small protein messengers which aid in cell signalling. They are defined in the 5th edition of Janeway’s Immunobiology as, “ a term for any protein secreted by immune cells that affects the behaviour of nearby cells bearing appropriate receptors.“ Cytokines are produced by a host of immune cells, including leukocytes like natural killer cells and T-cells, as well as other cell types, like epithelial and endothelial cells. Regardless of where they are produced, their primary function is to facilitate communication between cells and enact change.
Many cytokines have names which begin with the word 'interleukin'. This is because cytokines were originally discovered in the context of signalling between (inter) immune cells (leukins). Interleukins can facilitate cell growth, differentiation, maturation, or proliferation, depending on the context.
Cytokines are key players in the generation, and later, inhibition of immune responses. Pro-inflammatory cytokines like IL-1 and TNFα can drive an inflammatory response forward and recruit appropriate cells to a site. These cytokines can play a pathogenic role in chronic or acute inflammatory diseases. Anti-inflammatory cytokines like IL-10 and TBF-β have the opposite effect, and are implicated in the resolution of inflammation and the restoration of homeostasis. However, they too can play a pathogenic role when their inflammatory-suppressing action is used to create a tolerogenic immune environment in tumours.
Because cytokines are primarily peptides or otherwise hydrophilic, they cannot cross cell membranes and instead rely on the receptors. The cytokine-receptor interaction has been the target of considerable therapeutic interest. In fact, some of the most popular drugs on the market are biologics which act on cytokines. A notable example includes the anti-TNFα monoclonal antibody adalimumab, which works by binding and blocking the pro-inflammatory TNFα. Since the cytokine plays a role in the severity of such inflammatory diseases as rheumatoid arthritis, reducing the levels of soluble TNFα can significantly attenuate the immune response and halt further downstream effects.
Etanercept also acts on the cytokine TNFα and is a fine example of cytokine manipulation applied to a therapeutic context. Etanercept is a fusion protein modeled after the naturally occurring soluble TNF receptor. It is able to bind TNFα— effectively ‘mopping it up’ from the affected areas— and because of its unique protein composition it is much more robust and long-lasting in the bloodstream than unaltered soluble TNF receptors. Both it and adalimumab have met with impressive clinical and commercial success since their release.
Cytokines play complex and context-dependent roles in the immune system. A single cytokine can have vastly different effects depending on the cell type or signalling pathway activated. For example, IL-4 has been reported to be involved in airway inflammation in patients with allergic asthma, but it can also induce differentiation in naive helper T cells and facilitate their development into Th2 helper T cells. Another important interleukin, IL-2, is primarily produced by activated cytotoxic CD8+ T cells and active CD4+ helper T cells. IL-2 can promote the differentiation of immature T cells to regulatory T cells in the thymus, thus aiding in the resolution of inflammation and preventing autoimmune diseases. Rather paradoxically, IL-2 can also encourage T cells to differentiate into effector and memory T cells after initial exposure to their cognate antigen. Despite its generally helpful role, IL-2 has been implicated in psoriasis.
To learn more about cytokines and their diverse roles in biological systems, see our resources below!