EYRAplex: Human Cytokine storm (20‑plex)

Chemokine ligand 2 (CCL2), also called monocyte chemoattractant protein-1 (MCP-1) and JE, belongs to the CC chemokine family. CCL2 is secreted by a wide array of cells including monocytes, macrophages, dendritic cells, endothelial cells, astrocytes, and osteoblasts. In addition to its chemotactic properties, CCL2 is involved in processes of degranulation, upregulation of receptors, cell survival, and secretion of cytokines. Its presence in multiple tissues has been linked to various diseases such as Alzheimer's, diabetes, tuberculosis, osteoporosis, and cancer where CCL2 plays a role in tumor microenvironment.

CCL3, also known as MIP-1α (Macrophage Inflammatory Protein-1 alpha), is a chemokine primarily secreted by macrophages, dendritic cells, and activated T cells. Its main role in the immune system is to recruit and activate immune cells, particularly monocytes, lymphocytes, and natural killer (NK) cells, to sites of infection or inflammation. CCL3 also enhances immune responses by promoting cytokine production and facilitating cell-to-cell communication, playing a crucial role in both innate and adaptive immunity.

The CCL4 chemokine plays a role in inflammation and chemotaxis. CCL4 is produced by a variety of cells, including monocytes, NK cells, and T cells. It binds to CCR5. This receptor is expressed by T cells and macrophages (among others). CCL4 is involved in the host response to a wide range of pathogens, it's been especially studied in HIV. Furthermore, dysregulation of CCL4 expression has been associated with various pathological conditions, including autoimmune diseases and cancer. CCL4 is also named macrophage inflammatory protein-1β (MIP-1β). 

CD25 is expressed by activated T cells, B cells, and monocytes. Tregs, responsible for regulating immune tolerance, express the highest amounts of CD25. CD25 is the IL-2 receptor α chain, which functions as one subunit of the high-affinity variant of the IL-2 receptor. When cleaved off by proteases, the soluble receptor (sIL-2Rα) is released extracellularly. Soluble CD25 has a low affinity for IL-2 and can function either as a decoy receptor reducing the activity of IL-2 or by enabling trans presentation to cells expressing the dimeric, intermediate-affinity IL-2R. Increased levels of soluble CD25 indicate ongoing immune responses, and therefore CD25 has been investigated as a biomarker for disease. For example, elevated sCD25 levels have been associated with autoimmune disorders, severe COVID-19, and some types of cancer. 

Granulocyte macrophage-colony stimulating factor (GM-CSF) can be secreted by T cells, macrophages, endothelial cells, and fibroblasts. GM-CSF stimulates the survival and functional activities of myeloid, that is, monocytes, macrophages, DCs, neutrophils, and eosinophils. It also stimulates the differentiation and proliferation of hematological progenitors.

Interferon-γ (IFN-γ) is the only type II interferon. This proinflammatory cytokine is secreted by activated T cells and NK cells. It activates macrophages and endothelial cells and regulates immune responses by affecting APCs, T cells, and B cells. Production of IFN-γ by helper T cells and cytotoxic T cells is a hallmark of the Th1-type phenotype. Thus, high-level production of IFN-γ is typically associated with effective host defense against intracellular pathogens.

Interleukin 1α (IL-1α) is a pro-inflammatory cytokine primarily produced by monocytes, macrophages, and neutrophils. IL-1α induces acute phase responses such as fever, T cell, and macrophage activation. 

Interleukin 1ß (IL-1ß) is a proinflammatory cytokine and inducer of acute phase responses. IL-1ß is produced primarily by monocytes, macrophages, and dendritic cells after induction by microbes.
 

Interleukin 2 (IL-2) is predominantly produced by activated T cells. IL-2 promotes the proliferation, differentiation, and survival of antigen-activated T cells and NK cells. After antigen stimulation, the cytokine also promotes the differentiation of T cells into effector and memory T cells. Therefore IL-2 plays an important role in the body's response to infection. IL-2 is also key to tolerance, as it promotes the differentiation of certain immature T cells into regulatory T cells in the thymus, ultimately preventing autoimmune diseases. 

Interleukin 4 (IL-4) is produced primarily by Th2 cells, mast cells, eosinophils, and basophils. IL-4 was first identified to costimulate B cell growth; the cytokine is essential for B cell secretion of IgE and augments the production of IgG1 in vivo. In addition to regulating B cell growth and immunoglobulin secretion, IL-4 also affects T cells. In vitro, IL-4 promotes T cell growth and can induce cytolytic T cell activity. IL-4 also induces the differentiation of naive CD4 T cells into Th2 cells, which are characterized by their capacity to secrete the cytokines IL-4, IL-5, and IL-10 upon activation, while simultaneously inhibiting the generation of Th1 cells.

Interleukin 5 (IL-5) is a pleiotropic cytokine primarily produced by T and NK cells.  IL-5 specifically controls the survival, differentiation, and chemotaxis of eosinophils. But initially, IL-5 was characterized by its ability to support the growth and terminal differentiation of B cells.

Interleukin 6 (IL-6) is a pleiotropic cytokine produced by many different cell types and plays a role in a wide range of functions, such as immune responses, acute-phase reactions, and hematopoiesis. Among other things, it augments antibody production from activated B cells in vitro.

Interleukin 8 (IL-8) is a proinflammatory cytokine produced by different types of cells, including monocytes, macrophages, and endothelial cells. Inflammatory stimuli, such as LPS, strongly induce IL-8 production by monocytes.

Interleukin 10 (IL-10) is a pleiotropic cytokine produced by activated T cells and monocytes. It can modulate the functions of immune responses in both a stimulatory and an inhibitory way. IL-10 is thereby involved in the regulation of immune reactions and inflammatory responses.

Interleukin 13 (IL-13) is produced by Th2-type cells, mast cells, and NK cells in response to activation. It regulates the secretion of IgE by B cells and the Th2-type cell development and suppresses inflammatory responses by regulation of macrophage function.

Interleukin 17A (IL-17A) is a potent proinflammatory cytokine produced by activated Th17 (T helper 17) cells and certain cells belonging to the innate immune system. In mice, IL-17 has also been shown to be produced by activated CD8 T cells and γδ T cells. Th17 cells play an important role in autoimmune diseases and protection against bacteria and fungi. IL-17A acts on a broad range of cell types to induce the expression of cytokines, chemokines, and metalloproteinases. As a result, secretion of IL-17A promotes inflammatory responses, which leads to the recruitment of neutrophils, enhancement of antibody production, and activation of T cells. Increased expression of IL-17A is seen in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. It is also associated with asthma, psoriasis, cancer, and transplant rejection.

Interleukin 17F (IL-17F) is a homodimer composed of two IL-17F subunits. IL17-F is a member of the IL-17A protein family. This proinflammatory cytokine is produced by activated Th17 (T helper 17) cells and certain cells of the innate immune system. Th17 cells play an important role in protection against bacteria and fungi. IL-17F contributes to the pathogenesis of inflammatory and autoimmune diseases, for example, psoriasis.

Interferon gamma-induced protein 10 (IP-10) secretion is induced by IFN-γ, TNF-α, and IL-1β. This proinflammatory cytokine is produced by monocytes, endothelial cells, and fibroblasts. The interferon gamma-induced protein 10 recruits lymphocytes to sites of infection and increases the expression of MHC class I molecules. In addition to chemotaxis, IP-10 is also involved in the differentiation and activation of peripheral immune cells, regulation of cell growth, apoptosis, and modulation of angiostatic effects. The binding of IP-10 (CXCL10) to the CXCR3 receptor causes the downstream activation of the phospholipase C-dependent pathway, an increase in intracellular calcium production, and actin reorganization. 

Transforming growth factor β1 (TGF-β1) is secreted by many cells and controls functions such as cell growth, cell differentiation, proliferation, and apoptosis. The cytokine TGF-β1 is an important regulator of immune functions. Specifically for T cells, TGF-β1 promotes the differentiation of regulatory T cells, preventing IL-1- and IL-2-dependent proliferation of activated T cells, the activation of helper T cells, and cytotoxic T cells. TGF-β1 is secreted in a latent, biologically inactive form, non-covalently linked with a latency associated protein (LAP). 

Tumor necrosis factor (TNF), also known as TNF-α, is produced by many different cell types, e.g., monocytes, macrophages, T cells, and B cells. Among the many effects of TNF-α are protection against bacterial infection, cell growth modulation, immune system regulation, and involvement in septic shock.