The onset, activation and regulation of inflammation, innate and specific immune response and also of acute phase reactions are largely due to small polypeptides, generically called cytokines which bind to specific receptors on target cells.
Cytokines are secreted by many and maybe all kinds of cells, especially by activated lymphocytes and macrophages in response to various stimuli.
Cytokine synthesis is a short-lived phenomenon, tightly controlled and strictly dependent on the presence of foreign agent or stimulus; once synthesized, they are rapidly secreted, act and are utilized without any accumulation. Moreover, given the high affinity of their receptors, a minimum dose of cytokines is required to have a biological effect.
Cytokines may have an autocrine action, when interact with receptors of the same cell that produced them, or a paracrine action, when act on neighboring cells; moreover they can have an endocrine action, similarly to “classic” hormones, when they pass in blood and can reach and act on distant cells and tissues.
Rarely cytokines act alone but often different cytokines are secreted together and they influence each other. Cytokines can act on different cell types (pleiotropism) and determine, depending on the case, similar or different responses; on the other hand, it is also possible that different cytokines can act on the same cell by determining similar effects (redundant effect).
Some cytokines can cooperate (synergistic effect) or, conversely, may antagonize (antagonistic effect). The ability of a cytokine to enhance or suppress the activation of other cytokines is of fundamental importance in the positive or negative regulation of the mechanisms of the immune or inflammatory response.
In order to act, cytokines bind to specific cell surface receptors and this link determines the signal transmission from the cytoplasm to the nucleus that is mediated by the expression of genes that might be quiescent.
Since cytokines have so important and different activities, they should also have efficient control mechanisms to prevent an uncontrolled action causing pathological effects. These receptoral control mechanisms include: 1) reduction of receptor expression; 2) decoy receptor that do not transmit signal; 3) soluble receptors due to the clivage of the extracellular domain of the receptor, which bind cytokines outside the cell; 4) receptor antagonists that competes with cytokine in binding receptor and do not actives the signal transmission; 5) antagonist cytokines with inhibitory activity (anti-inflammatory cytokines) are able to decrease the synthesis of activation receptors or increase the control mechanisms.
The cytokines involved in innate and specific immunity are classified in some main groups:
- Interleukins (IL-); a wide and heterogenous group of cytokines with a broad functions and effect on leukocytes. As of 2017, 38 interleukins are discovered and numbered depending on this.
- Tumoral Necrosis Factor (TNF-): are two related cytokines, one mainly produced by macrophages (TNF-α) and the other by T lymphocytes (TNF-β). Their name ("Tumor Necrosis Factor") derives from their ability to induce apoptosis (programmed cell death) in cancer cells, however, TNFα has numerous pro-inflammatory and immune function;
- The Interferons (IFNs) are the Type 1 IFNs (IFN-α, IFN-β) and Type II IFNs (IFN-γ). They are proteins synthesized during innate response against virus (Type I IFNs) and by immune cells during Th1 response (IFNγ).
- Growth Factors: many cytokines have important effects on proliferation of immune cells, such as IL-2, IL-3, IL-5, IL-7, and also some CSF (“Colony Stimulating Factor”) as G-CSF, M-CSF and GM-CSF. TGF β has an immunoregulatory/inhibitory effect;
- Chemokines are a wide family of polypeptides having a role in the recruitment and chemotaxis of leukocytes and lymphocytes during inflammation and immune response. The main chemokines are: 1) IL-8 is specific chemokine for neutrophils; 2) MCP1 recruits and activates monocytes; 3) MIP-1a recruits monocytes, NK and T lymphocytes; 4) RANTES recruits monocytes, NK and T lymphocytes, basophils and eosinophils; 5) Eotaxin recruits eosinophils.
Table 1. Cytokines grouped accordingly their main function in immunity
|Onset and maintenance of inflammatory/innate response||IL-1, TNF-α, IFN-α/β, IL-8, IL-6, IL-15, IL-18, IL-12|
|Specific Immunity regulation||DRIVING CYTOKINES
Th1 driving cytokines: IL-12, IL-18
Th2 driving cytokines: IL-4
Th17 driving cytokines: IL-6, IL-23
Th1 cytokines: IL-2, IFNγ
Th2 cytokines: IL-4, IL-5, IL-13
Th17 cytokines: IL-17, IL-21
Treg: IL-10, TGFβ
|Inflammatory/Immune cell recruitment||Chemokines (IL-8, MCP1, MIP-1, Rantes, Eotaxin)|
|Control and switching off inflammation and immunity||IL-10, TGFβ|
|Proliferation and differentiation of immune cells||GM-CSF, IL-2, IL-7, IL-15|
Table 2. Functions of the major cytokines involved in immunity regulation
|Cytokine||Main cell source||Functions|
|IL-1||Epithelial cells, infected cells, neutrophils, macrophages||Activation of inflammatory/innate cells and endothelial cells; fever induction|
|TNF-α||Epithelial cells, infected cells, neutrophil, macrophage, NK cells||Activation of inflammatory/innate cells and endothelial cells; endocrine effect; catabolic induction|
|IL-8||Epithelial, endothelial and innate cells||Recruitment and activation of neutrophils|
|IL-6||Endothelial cells, neutrophils, macrophage||Activation of inflammatory/innate cells and endothelial cells; endocrine systemic effect with catabolism induction|
|MCP1||Epithelial, endothelial and innate cells||Recruitment and activation of monocytes|
|IFNα/β||Infected cells||Antiviral activity; innate cells activation, adhesion molecules induction; increase of MHC expression on dentritic cells|
|IFNγ||NK cells, γ/δ T lymphocytes, Th1 lymphocytes, cytotoxic T lymphocytes (CTL)||Major role in the cell-mediated immunity against intracellular pathogen: activation of macrophages, NK cells, CTL, maintenance of Th1 differentiation.|
|IL-15||Dentritic cells||NK and NKT proliferation and activation; prolonged survival of memory T cells|
|IL-12||Dentritic cells, macrophages||Th1 induction|
|IL-18||Dentritic cells, macrophages||Th1 induction; proinflammatory activity|
|IL-17||Th 17 lymphocytes||Proinflammatory activity; recruitment and activation of neutrophils; increase of antimicrobial peptides|
|IL-22||Th 17 lymphocytes||Promotion of acute neutrophil-mediated inflammation together with IL-17|
|IL-10||M2 polarized macrophages; T reg lymphocytes, Th2-lymphocytes||Antiinflammatory and immunosuppression activity|
|TGFβ||T reg lymphocytes, Th2-lymphocytes||Antiinflammatory and immunosuppression activity|
|IL-2||T lymphocytes||Proliferation and activation of T and B cells; activation of NK cells|
|IL-4||Th2 lymphocytes||Th2 cytokine: stimulation and growth of B cells, induction of IgA and IgE secretion|
|IL-5||Th2 lymphocytes||Th2 cytokines involved in eosinophil production|