Cytokine is a general term used for small secreted proteins that are key modulators of inflammation. Cytokines are produced in response to invading pathogens to stimulate, recruit, and proliferate immune cells. Cytokines includes interleukins (IL), chemokines, interferons, and tumor necrosis factors (TNF). Cytokines are subdivided based on the nature of the immune response and the source of their production (Table 1) .
There are both pro-inflammatory and anti-inflammatory cytokines. The pro-inflammatory cytokines are secreted from Th1 cells, CD4+ cells, macrophages, and dendritic cells. They are characterized by production of several Interleukins (IL), IL-1, IL-2, IL-12, IL-17, IL-18, IFN-γ, and TNF-α. The key pro-inflammatory cytokines are IL-1, IL-6, and TNF-α. These cytokines signal via type I cytokine receptors (CCR1) that are structurally divergent from other cytokine receptor types. They are crucial for coordinating cell mediated immune response and play a critical role in modulating the immune system. Pro-inflammatory cytokines generally regulate growth, cell activation, differentiation, and homing of the immune cells to the sites of infection with the aim to control and eradicate the intracellular pathogens, including viruses .
IL-1 is subdivided in IL-1α and IL-1β. IL-1β is potent pro-inflammatory cytokine, induced mainly by lymphocytes, macrophages, and monocytes in response to microbial molecules. Upon viral infection, the pattern recognition receptors (PPR) and toll-like receptors (TLRs) are expressed which in turn lead to enhanced expression of IL-1β. IL-1β stimulate CD4+ cells and differentiate them towards Th17 cells. In addition to the stimulatory effect of the IL-1 family, there are also members (IL-1R, a and 2) that can inhibit or suppress the IL-1 cytokine expression. IL-1Ra is secreted from neutrophils, macrophages, monocytes, and hepatocytes aiming to decrease the inflammation. However, the expression of IL-Ra needs to be expressed up to 1,000-fold in order to efficiently inhibit or suppress the expression of IL-1β .
IL-6 is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events, such as regulating cell growth, as well as gene activation, proliferation, survival, and differentiation. IL-6 is produced by a variety of cell types including monocytes, fibroblast, and endothelial cells. Upon stimulation, IL-6 is secreted by many additional cell types including macrophages, T cells, B cells, mast cells, glial cells, eosinophils, keratinocytes, and granulocytes. IL-6 stimulates several types of leukocytes and the production of acute phase proteins in the liver. It is particularly important in inducing B-cells to differentiate into antibody-forming cells (plasma cells). Binding of IL-6 to its receptor initiates cellular events including activation of JAK (Janus Kinase) kinases and activation of Ras-mediated signaling.
Like other Th1 pro-inflammatory cytokines, TNF-α has an important role comprising the inflammatory response both locally and in the circulation. TNF-α triggers the expression of vascular endothelial cells as well as enhances the leukocyte adhesion molecules that stimulate immune cell infiltration. It has a crucial role in early response against viral infection by enhancing the infiltration of lymphocyte to the site of infection [3, 4].
Chemokines are cytokines with chemotactic activities. They are classified into four main subfamilies including CXC, CC, CX3C, and XC chemokines with both structural and functional differences. They play a crucial role in regulating the movement and localization of lymphocytes and a subset of dendritic cells. The CXC chemokines are mainly involved in the recruitment of immune cells to the site of inflammation and the homeostatic chemokines that mediate homeostatic migration and homing of lymphocytes. However, some chemokines have also dual-function and can be inflammatory and/or anti-inflammatory depending on the site of expression and concentration .
Figure 1. Cytokine network. Immune cells communicate with other immune cells by cytokines, which control proliferation, differentiation, and function. Furthermore, they are involved in processes of inflammation, hematopoiesis, neurogenesis, embryogenesis, and oncogenesis. Unlike hormones, cytokines are not stored in glands as pre-formed molecules but are rapidly synthesized and secreted mostly after stimulation. Cytokines frequently affect the action of other cytokines in an additive, synergistic, or antagonistic manner.
|Cytokine||Classification||Main Sources||Receptor||Target Cell||Major Function|
|Erythropoietin||Endothelium||EpoR||Stem cells||Red blood cell production|
|G-CSF||Pro-inflammatory||Fibroblasts, endothelium||CD114||Stem cells in BM||Granulocyte production|
|GM-CSF||Adaptive immunity||T cells, macrophages, fibroblasts||CD116, CDw131||Stem cells||Growth and differentiation of monocytes, and eosinophil, granulocytes production|
|IL-1||Pro-inflammatory||Macrophages, B cells, DCs||CD121a||B cells, NK cells, T-cells||Pyrogenic, pro-inflammatory, proliferation and differentiation, BM cell proliferation|
|IL-2||Adaptive immunity||Th1 cells||CD25||Activated T and B cells, NK cells||Proliferation of B cells, activated T cells, NK cell function|
|IL-3||Adaptive immunity||T cells||CD123, CDw131||Stem cells||Hematopoietic precursor proliferation and differentiation|
|IL-4||Adaptive immunity||Th Cells||CD124||B cell, T cell, macrophages||Proliferation of B and cytotoxic T cells, enhances MHC class II expression, stimulates IgG and IgE production|
|IL-5||Adaptive immunity||Th2 Cells and mast cells||CDw125, 131||Eosinophils, B-cells||B-cell proliferation and maturation, stimulates IgA and IgM production|
|IL-6||Pro-inflammatory||Th Cells, macrophages, fibroblasts||CD126, 130||B-cells, plasma cells||B-cell differentiation|
|IL-7||Adaptive immunity||BM stromal cells, epithelial cells||CD127||Stem cells||B and T cell growth factor|
|IL-8||Pro-inflammatory||Macrophages||IL-8R||Neutrophils||Chemotaxis for neutrophils and T cells|
|IL-9||Adaptive immunity||T cells||IL-9R, CD132||T cell||Growth and proliferation|
|IL-10||Anti-inflammatory||T cells, B cells, macrophages||CDw210||B cells, macrophages||Inhibits cytokine production and mononuclear cell function|
|IL-11||Pro-inflammatory||BM stromal cells||IL-11Ra, CD130||B cells||Differentiation, induces acute phase proteins|
|IL-12||Anti-inflammatory||T cells, macrophages, monocytes||CD212||NK cells, macrophages, tumor cells||Activates NK cells, phagocyte cell activation, endotoxic shock, tumor cytotoxicity, cachexia|
|IL-17||Pro-inflammatory||Th17 cells||IL-17R||Monocytes, neutrophils||Recruits monocytes and neutrophils to the site of infection. Activation of IL-17 in turn activate downstream of many cytokines and chemokine, such as IL‐1, IL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1|
|IL-18||Pro-inflammatory||Macrophages, dendritic cells, and epithelial cells||CD218a (IL-18Ra)||Monocytes and T cells||Recruits monocytes and T lymphocytes. Synergist with IL-12 in the induction of IFN- γ production and inhibition of angiogenesis.|
|IL-22||Anti-inflammatory||Activated T-cells and NK cells||IL-22R||Stromal and epithelial cells||Stimulation of cell survival, proliferation|
|IL-37 (1L-1F7)||Anti-inflammatory||B-cells, NK cells, and monocytes||CD218a (IL-18Ra) and potentially SIGGR||Believed to act as a negative regulator inside the cell|
where it interacts with SMAD3 that is activated downstream of TGFβ activity.
|IL-38 (IL-1F10)||Anti-inflammatory||B cells and macrophages||IL-1R1||Unknown|
|IFN-α||Pro-inflammatory||Macrophages, neutrophils, and some somatic cells||CD118 (IFNAR1, IFNAR2)||Various||Anti-viral|
|IFN-β||Pro-inflammatory||Fibroblasts||CD118 (IFNAR1, IFNAR2)||Various||Anti-viral, anti-proliferative|
|IFN-γ||Pro-inflammatory||T Cells and NK cells||CDw119 (IFNG R1)||Various||Anti-viral, macrophage activation, increases neutrophil and monocyte function, MHC-I and -II expression on cells|
|M-CSF||Adaptive immunity||Fibroblasts, endothelium||CD115||Stem cells||Monocyte production and activation|
|TGF-β||Anti-inflammatory||T cells and B cells||TGF-βR1, 2, 3||Activated T and B cells||Inhibits T and B cell proliferation, inhibits hematopoiesis, promote wound healing|
|TNF-α||Pro-inflammatory||Macrophages||CD120a,b||Macrophages||Phagocyte cell activation, endotoxic shock|
|TNF-β||Pro-inflammatory||T Cells||CD120a,b||Phagocytes, tumor cells||Chemotactic, phagocytosis, oncostatic, induces other cytokines|
|Abbreviations: IL; interleukin, TNF; tumor necrosis factor, IFN; interferon, G-CSF; granulocyte colony stimulating factor, GM-CSF; granulocyte macrophage colony stimulating factor, M-CSF; macrophage colony stimulating factor, TGF; transforming growth factor, CD; cluster of differentiation; CDw; cluster of differentiation designated by only one monoclonal antibody, BM; bone marrow, DC; dendritic cells|
During viral infections, like SARS-CoV-2, RSV, Parvovirus B19, and Influenza, the level of the pro-inflammatory cytokines is elevated and decreased upon clearance of the virus [1, 5]. Influenza A and SARS-CoV-2 virus infections lead to high replication of the virus in respiratory epithelial cells. In addition, the infection itself mediates an aggressive inflammatory response that itself can cause damage of lung cells. This contributes to a high number of apoptotic cells that are phagocyted by resident macrophages. Upon phagocytosis, macrophages release pro-inflammatory cytokines that recruit other immune cells and cause acute inflammation in the lung tissues, provoking fever and enhanced fibrosis.
Apoptotic cells are also known to release pathogen associated molecular patterns (PAMP) and bind pattern recognition receptors (PRRs) which lead to the activation of TLR2, TLR3, or TLR4 [7, 8]. This binding increases levels of the local IL-1β and IL-8 and recruit macrophages and monocytes to remove the remaining fragments of the apoptotic cells, but simultaneously this will recruit other immune cells to the site of infection. Macrophages will present the viral peptides to T-helper cells that will activate and differentiate to produce Th1 pro-inflammatory cytokines associated with Th17 cell subsets. That in turn releases a wave of local IL-6, IFN-γ, MCP1, and IP-10 (CXCL10) into the circulation.
IL-12 and IL-8 are other cytokines that are produced to enhance the IFN-γ production which attracts monocytes and T lymphocytes but not neutrophils (in SARS-CoV-2), in order to induce apoptosis and eliminate the infected cells. The recruited cytotoxic T lymphocytes clear the infection and the immune response retreats to the haemostasis condition .
The regulatory T cells (Treg, CD4+, CD25+, Foxp3+ cell) are among T cells recruited to the site of infection. They are important mediators for immune regulation and control the level of cellular immune responses to the viral infections. Treg secretes IL-10, an important regulatory cytokine that inhibit the excessive T cells response and balance the immune response .
As described above, a primary viral infection is associated with increased levels of Th1 pro-inflammatory cytokines, chemokines, and interferons. However, regulation of the cytokine secretion is crucial for keeping the haemostasis of the immune system. A misregulated cytokine production can lead to severe inflammation. An aberrant pro-inflammatory cytokine profile or a shift in the balance of the Th1/Th2 cytokine response has been suggested to play a role in the control of the viral infection and lead to viral persistence [Parvovirus]. Not only the expression but a balance in the kinetics of the pro-inflammatory and Th1/Th2 cytokine pattern is key to viral clearance and haemostasis of the immune system.
Several interleukins are involved in the regulation of the inflammation by suppressing the innate and acquired immunity. IL-10, IL-37, and IL-38 are among some which regulate the activation and proliferation of the T cells by binding to the inhibitory receptors, such as IL-18Ra (IL-R5) and IL-1R6. IL-38 is produced by B cells and macrophages and inhibits IL-1, IL-6, IL-17, IL- 22, and TNF [1, 11].
Misregulation of the immune response may lead to a massive increase of cytokine and chemokine levels which is referred to as cytokine release syndrome or cytokine storm. This phenomenon is characterized by an aggressive pro-inflammatory response in combination with an insufficient anti-inflammatory response, which results in the loss of homeostasis of the immune response .
Multiple causes can lead to a cytokine storm, which recently came into focus in medical research because it is believed to be a major cause for morbidity and mortality in SARS-CoV-2 infections. The SARS-CoV-2 virus may result in severe lung damage, which is caused not primarily by viral spreading but by overstimulation of the immune-system leading to a massive and uncontrollable inflammation .
Several pathologies involving a cytokine storm are described, like sepsis, toxic shock syndrome (TSS), macrophage activation syndrome (MAS), hemophagocytic lymphohistiocytosis (HLH), and malignancy associated syndrome of hyperinflammation (MASH) . The key factors identified in pathologies involving a cytokine storm are TNF-α, interferons, IL-1β, MCP-1 (CCL2), and most importantly IL-6 . Many more cytokines and chemokines play an important role in a cytokine storm, as summarized in the table Protein Biomarkers for Cytokine Release Syndrome in the ProcartaPlex Multiplex Cytokine Assay.
In the proposed pathogenesis of cytokine storm, activation of mainly T cells or lysis of immune cells induces a release of IFN-γ or TNF-α. This leads to the activation of macrophages, dendritic cells, other immune cells, and endothelial cells. After activation, these cells further release pro-inflammatory cytokines. Large amounts of IL-6 are produced by macrophages and endothelial cells, activating T cells and other immune cells and thereby creating a positive feedback-loop that results in a cytokine storm, inducing the release of many more cytokines and chemokines but also upregulating acute phase proteins.
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