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Cytokines

Cytokines are small cell signaling protein molecules secreted by numerous cells of the immune system and glial cells of the central nervous system, which are signaling molecules allowing intracellular communication.

Refers to a wide collection of secreted factors that belong to different structural families and use different types of receptors and distinct modes of signaling.

Cytokines have a key role in coordinating antimicrobial effector cells and providing regulatory signals that direct, amplify, and resolve the immune response.
 
Cytokine response requires a balance between sufficient cytokine production to eliminate  a pathogen and avoidance of hyperinflammatory response in which in overabundance of cytokines causes clinically significant collateral damage.

Classified as proteins, peptides, or glycoproteins at our produced by a variety of cells throughout the body.

Include interleukins and interferons, immunomodulating agents, erythropoietin, growth hormone and prolactin.

Cytokines including tumor necrosis factor , interleukin-1, interleukin-6, and interferon-gamma, are produced by inflammatory cells within the first hours after the onset of inflammation.

Cytokines restrict erythropoiesis directly and indirectly, and shorten the red blood cell lifespan.

Cytokines have short half fives, which normally prevents them from having effects outside lymphoid tissue and sites of inflammation.

Produced by virtually all nucleated cells, but especially by endo/epithelial cells and macrophages producing IL-1, I L.-6, and TNF-alpha.

Activities may be autocrine or paracrine in terms of chemotaxis and endocrine as a pyrogen.

Have a role in embryogenesis.

Cytokines are small proteins (~5–20 kDa) that are important in cell signaling.

Cytokines are peptides

They cannot cross the lipid bilayer of cells to enter the cytoplasm.

Cytokines are involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors.

They are not hormones or growth factors.

Hormones circulate at higher concentrations and tend to be made by specific kinds of cells.

Sustained production of cytokine may lead to elevated circulating levels that may be required to appropriately control some disseminated infections.
Increased levels of cytokines can have systemic effects and cause collateral damage to a vital organ system.

They are produced by a broad range of cells.

Cells that can produce cytokines include: immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, endothelial cells, fibroblasts, and various stromal cells.

Cytokines may be produced by more than one type of cell.

Cytokines act through receptors.

Have a vital role in the immune system.

They can modulate the balance between humoral and cell-based immune responses.

Cytokines regulate the maturation, growth, and responsiveness of cell populations.

Some cytokines enhance or inhibit the action of other cytokines.

Cytokines are immunomodulating agents.

Some immunomodulating effects of cytokines are systemic rather than local.

They are important in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

Hormones circulate in nanomolar (10-9 M) concentrations that usually vary by less than one order of magnitude.

Some cytokines circulate in picomolar (10-12 M) concentrations that can increase up to 1,000 times during trauma or infection.

Cytokines are produced by a widespread number of cellular sources .

Virtually all nucleated cells, but especially endothelial cells, epithelial cells and macrophages are producers of IL-1, IL-6, and TNF-α.

Many cells near the interface with the external environment produce cytokines.

Contrarily, hormones are secreted from discrete glands.

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action.

The majority of these are produced by T-helper cells.

Lymphokines are produced by lymphocytes.

Monokines: produced exclusively by monocytes.

Interferons: involved in antiviral responses.

Colony stimulating factors: support the growth of cells.

Chemokines: mediate chemotaxis between cells.

Cytokines can be classified into four structural types:

The four-α-helix bundle family: member cytokines have three-dimensional structures with four bundles of α-helices.

This family, in turn, is divided into three sub-families:

the IL-2 subfamily

the interferon (IFN) subfamily

the IL-10 subfamily.

The IL-2 subfamily, is the largest and contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO).

The four-α-helix bundle cytokines can be further grouped into long-chain and short-chain cytokines.

More useful is a clinical classification outside of structural biology divides immunological cytokines into those that enhance cellular immune responses, type 1 (TNFα, IFN-γ, etc.), and type 2 (TGF-β, IL-4, IL-10, IL-13, etc.), which favor antibody responses.

Cytokines in one of these two sub-sets tend to inhibit the effects of those in the other.

Inflammatory cytokines are induced by oxidative stress.

Cytokines trigger the release of other cytokines

Cytokines can lead to increased oxidative stress making them important in chronic inflammation, as well as immune responses, such as fever and acute phase proteins of the liver.

They have an anti-inflammatory role and are a possible therapeutic treatment for pain from inflammation or peripheral nerve injury.

Cytokine receptors have been directly linked to certain debilitating immunodeficiency states.

A classification of cytokine receptors provides several pharmacotherapeutic targets.

Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the body, and share structural homology with antibodies, cell adhesion molecules, and even some cytokines.

Hemopoietic Growth Factor (type 1) family.

Interferon (type 2) family, whose members are receptors for IFN β and γ.

Tumor necrosis factors (TNF) (type 3) family.

Interleukin-17 receptor (IL-17R) family.

Each cytokine has a matching cell-surface receptor., whose cascades of intracellular signaling can alter cell functions.

Altered cell signaling can up-regulate and/or downregulate several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition.

The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular level, the presence of the complementary receptor on the cell surface, and downstream signals activated by receptor binding.

The factors can vary by cell type.

Many cytokines appear to share similar functions.

Cytokines that bind to antibodies have a stronger immune effect than the cytokine alone.

Inflammatory cytokines cause an IL-10-dependent inhibition of T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.

They are vital for fighting off infections and in other immune responses, but can become dysregulated and a source of pathology in inflammation, trauma, sepsis and hemorrhagic stroke.

Its adverse effects have been linked to many disease states and conditions including schizophrenia, major depression, Alzheimer’s disease and cancer.

Normal tissue integrity is preserved by adhesion molecules and secreted cytokines.

Cytokine over secretion can manifest as a cytokine storm associated with severe events manifested by a systemic inflammatory response syndrome and multi organ failure.

Cytokine storm felt to be responsible for high number of deaths in individuals with healthy immune systems producing a stronger immune response.

Some cytokines have been developed using recombinant DNA technology into therapeutic agents:

Bone morphogenetic protein (BMP),

Erythropoietin (EPO),

Granulocyte colony-stimulating factor (G-CSF),

Granulocyte macrophage colony-stimulating factor (GM-CSF)

Interferon alfa, Interferon beta,

Interleukin 2 (IL-2),

Interleukin 11 (IL-11)

Interferon gamma.

Cytokines and chemokines play a very important role in embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems.

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