CYTOKINES

What are cytokines? What is their role in immune response? What is a cytokine storm that is believed to cause death in Corona? We will try to find out answers to all these questions in this article, further, we will focus on the IL-17 signal transduction pathway.

Cytokines are glycoproteins that are involved in cell-to-cell communication. Cytokines are secreted by various blood cells. These are low molecular weight, proteins that are involved in the immune response.

 Properties of cytokines based on action

 Cytokines can be autocrine, paracrine, or endocrine. Autocrine cytokines are secreted by the cell on which they act upon. Paracrine cytokines act on neighboring cells. Endocrine cytokines act on distant cells. These are transported through the circulatory system

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 Cytokines show Redundancy, Synergy, Antagonism, Cascade induction 

Classification of cytokines

 Most of the cytokines have been named based on the cell that produces them for example lymphokines are the cytokines secreted by lymphocytes, monokines are the cytokines secreted by monocytes or macrophages.

Classification of cytokines

Broadly cytokines are divided into 5 different classes based on the receptor they use and their broad function.

Interleukins are the cytokines that are secreted by one lymphocyte and affect other lymphocytes

Interferons are the cytokines that are secreted In response to some viral infections the effect on the infected cells.

Tumor necrosis factor effect on the cancer cells. They kill the cancerous cells.

Chemokines are the cytokines that show chemotaxis. They invite cells and molecules to the site of inflammation.

G-CSF, GM-CSF, M-CSF are growth factors secreted by granulocytes, granulocyte macrophages, or macrophages, thus their name is granulocyte colony-stimulating factors, granulocyte-macrophage colony-stimulating factors, and macrophage colony-stimulating factors respectively. These are involved in cell recruitment and proliferation i.e. T-cell, B-cell proliferation.

 Cytokine can be part of innate immunity or adaptive immunity

 Cytokines of innate immunity

These include interleukin 1, tumor necrosis factor-alpha, interleukin 12(IL-12), interleukins 6(IL-6), interferon-alpha(INF-a), interferon-beta(INF-b), These cytokines are secreted by monocytes, macrophages, dendritic cells or epithelial cells, or fibroblast cells.

 Cytokines of adaptive immunity 

These include cytokines that are secreted by T cells i.e. T helper cells or T helper 2 cells. These include interleukin-2, interleukin-4, interleukin 5 interleukins 25, TNFβ, interferon-gamma these are involved in the T cell effector system of adaptive immunity, which is the activated T helper cell and  T cytotoxic cell or they are involved in the production of antibodies by B cells.

 Cytokines receptors

 These are surface molecules of effector cell receptors that fall in 5 different families.

GM-CSF receptor family act upon hematopoietic stem cells and progenitor cells and activates monocytes Induce megakaryocytes differentiation all these cytokines induce eosinophil proliferation, basophil degranulation, and release of histamine. GM CSF receptor subfamily which has a beta subunit common.  

 Immunoglobin superfamily receptors interact in antibodies have a single large protein that has multiple domains.

 

Class 1 cytokines receptor family is also known as hematopoietic in receptor family. Class 1 cytokines receptors have conserved four cysteine Residue and conserved tryptophan Serine- any amino acid- tryptophan- serine domain (WSXWS).

 Class -2 cytokines receptors have four cysteine Residue which is conserved but lacks WSXWS cytokine. Class-2 cytokines receptor family known as interferon receptor family, tumor necrosis factor receptor family

IL-2 receptor subfamily that has a common Gamma subunit. Other subunits of these receptors are made of different alpha and beta subunits.

 IL- 6R Subfamily  has gp-130 protein common which indicates they  have common signaling pathway these cytokines stimulates megakaryocyte maturation and platelet production

 Chemokines receptor family receptors are different from other families. They are small in size and have single that span across the membrane. At the cytoplasmic end, these are associated with G-protein.

 IL-2 signal transduction subfamily is consists of a heterotrimer that consists of Alpha, Beta, and Gamma subunits, of this Gamma subunit, is common for all the other interleukins receptors that are identical to IL-15, IL-7, IL-9, IL-4. Gamma subunit is signal transduction subunit. x-linked severe combined immunodeficiency XSCID occurs due to loss of function of the cytokine receptor of the IL-2 subfamily. The signaling pathway involves protein phosphorylation their dimerization and activation.

 Receptors IL-2 receptors are involved in Tcell proliferation alpha and gamma subunit consists of conserved for cysteine Residue, alpha subunit however is different in IL-2 receptors. The alpha subunit is only expressed by the activated T cells. When all three subunits alpha, beta, gamma are present they form high-affinity receptors.

 Alpha- gamma subunits are constitutively expressed. Alpha and Beta chains are more restricted Tcell and enhanced after antigen has activated the Tcell lymphocytes this ensures that only antigen-activated CD4 + or CD8 + cells will Express high-affinity interleukin-2 receptor.

IL-2 signal transduction pathway involved binding of the cytokine to gamma subunit, Alpha- Beta subunit of the cytokines receptor form dimer, this dimerization of cytokines receptor that leads to activation of Janus kinase.

 The tyrosine kinase enzymes activated JAK create a docking site for STAT(Signal Transducers and Activators of Transcription) which is a transcription factor its phosphorylation occurs at a specific tyrosine residue. The phosphorylated STAT proteins now form a dimer.

 It now acts as an activated transcription factor that is translocated to Nucleus where it binds to a specific gene to enhance its transcription. STAT is a signal transducer and activator of transcription

IL-2 signal transduction pathway.

IL-17 signal transduction pathway

IL-17 signal transduction pathway involved IL 17 receptor. This receptor is a heterotrimer. Which has a IL- 17 RA, a IL- 17RA,17RC. This receptor when binding with IL-17 interleukin activates and enzyme Act 1 which is a dimer associated with heat shock protein 90(Hsp90)  this enzyme activate TRAF6 protein. This protein is involved in three different Pathways in which it activates C/EBP beta and MAP kinase(involved in cell division) and NF Kappa dimer.MAP kinase through another protein AP-1 is involves the activation of several genes present in the nucleus. These genes are required for cell division, proliferation, or differentiation. These three different Pathways have three different effects they may synthesize some new cytokines that are involved in inflammatory (IL-6, IL-4, TNFalpha ) response. They may synthesize tumor necrosis factors that are involved in Cancer response or they may synthesize chemokines further they may recruit Th2 helper cells for adaptive immunity response.

IL-17 SIGNAL TRANSDUCTION PATHWAY

CYTOKINE STORM AND COVID RELATED DEATHS

Cytokines Storm is also referred to as hypercytokinemia. Cytokine Storm has been seen in various infectious diseases and most recently in the case of severe Covid19 infections. In general cytokine storms result in acute inflammation which has 5 different symptoms such as redness, swelling, heat, pain, and loss of function. Redness is due to inflammation which is a host reaction against some infection. 

This inflammation allows the plasma protein and leukocyte to reach the site of infection. This is a normal reaction, however, during cytokines Storm, various inflammatory cytokines are produced in excess they may result in organ failure or multiple organ failure and may ultimately result in the death of the patient.

 Inflammatory cytokines are IL-6, IL-4, IL-2, TNF- a, and chemokines CXCL10, CCL2. The excessive secretion of the cytokines has been observed in infectious diseases as well as in the case of SARS Cov-2, MERS Cov-2. The excessive secretion of the cytokine is a warning sign in case of Covid-19 infection they may result in immunopathogenic damage, that not only result in an ARDS(Acute Respiratory Distress Syndrome)  where lungs fail to supply oxygen to different organs that may cause excessive tissue damage, organ failure, and death( reference news medical life science).

THE 5 to 7 days is critical for cytokines storm in case of covid 80% of the patient tends to improve after this time only 20% patient may show severe pneumonia and approximately 2% will ultimately succumb this virus. The use of a range of anti-inflammatory treatments has been taken in the case of covid-19 cytokines storm.

Cytokine antagonist

 The antagonist of cytokine block the receptor site so receptors would not be able to bind with particular cytokine this will stop the pathway of activation by cytokines of this soluble IL-2 receptor which is released in chronic T cell activation, can bind to IL-2 and thus this will now be unable to bind with membrane-bound receptor. This blocks the cytokine signal pathway.

 Some viruses also produce cytokine mimic for example Myxoma virus produce soluble gamma receptor

 Poxvirus produce soluble Gamma receptor

 Epstein Barr virus produces IL-10 homolog.