in this talk we're going to learn about cytokine receptors we will learn about different types of cytokine receptors and explain the main principles of cytokine signaling we will then learn about specific signaling pathways like the jack stat pathway as well as the interferon signaling pathway and finally we will learn about the outcome of cytokine signaling when pattern recognition receptors that are present in host cells as shown in the figure identify pamps that are present on pathogens signaling pathways get activated in the cell an outcome of the signaling pathway is the activation of a series of proteins and these proteins once activated can activate other proteins ultimately transcription factors get activated and they can bind to different regulatory sequences on dna and induce the expression of a variety of genes like cytokines chemokines and other molecules the cytokines and chemokines that are formed by the cell that is responding to the presence of a pamp are released in the environment these cytokines that are released in the environment can mediate their effects on target cells that will have receptors that can sense the presence of the cytokines in the environment these cytokines and chemokines can mediate physiological processes like inflammation and chemotaxis by binding to their appropriate target cells cytokines are able to mediate their effects by binding to cell surface receptors which are called a cytokine receptors if a host cell does not express cytokine receptors then that host cell cannot respond to cytokines present in the environment the cytokine receptors can be categorized into different groups and the type 1 cytokine receptor is utilized by the hematopoietin cytokines the type 2 cytokine receptor is utilized by the interferon cytokines and when we look at the type 1 and type 2 cytokine receptors they do not have any intrinsic enzymatic activity however both type 1 and type 2 cytokine receptors have kinases associated with them on the cytoplasmic part of the receptor and these kinases are called as janus kinases or jacks and play important roles in helping the cell sense cytokines are present in the environment the tnf family of cytokines are able to bind to the tnf receptor family and mediate their effects on the other hand the interleukin-1 family of cytokines are able to mediate their effects on host cells through the immunoglobulin type receptor family chemokines which are special types of cytokines that promote chemotaxis are able to mediate their effects through the g-protein-coupled receptor family when cytokines bind to the appropriate cytokine receptors on host cells they're able to activate many different signaling pathways as shown in this figure and these signaling pathways in turn result in the activation of proteins that allow the cell to respond to the presence of these cytokines chemokines also are able to bind to chemokine receptors and when they do they're able to activate g-protein-based signaling pathways because they're able to activate the trimeric g-proteins one of the outcome of cytokine signaling is the expression of different types of antimicrobial or antiviral molecules for example when interferon is able to bind to its appropriate receptor it activates transcription factors that result in the expression of genes called interferon stimulated genes or isgs the gene products of interferon stimulated genes are antiviral in nature and thus they're able to target different parts of the viral infection cycle including the entry and early replication steps as well as the late steps cytokine and chemokine signaling pathways can influence the differentiation growth as well as proliferation of cells in this figure we are able to see how a hematopoietic stem cell is able to form different types of blood cells through the actions of different types of cytokines thus these cytokines are able to regulate the differentiation of that multi-potent stem cell into appropriate differentiated immune cells like monocytes neutrophils t cells so on and so forth additionally cytokine signaling is also able to regulate the proliferation of cells so here we are able to see how the presence of cytokines are able to promote more immune cells to be made through cell division of these naive cells thus having more immune cells will help fight pathogens cytokine and chemokine signaling also helps in the reorganization of cytoskeletal proteins like microfilaments microfilaments are cytoskeletal fibers that are made through the polymerization of actin the microfilaments help maintain the cell shape and also allows the immune cell to move towards the pathogen the formation of microfilaments occurred through the polymerization of actin as well as the depolymerization thus cytokine signaling is able to modulate actin polymerization and depolymerization that allows the reorganization of the microfilaments the hematopoietin and interferon family of cytokines are able to bind to receptors that have no intrinsic kinase activity which essentially means that the receptors themselves do not have any kinase activity however they do have kinases that are associated with the receptors in the cytoplasmic region and these kinases are called as janus kinases or jacks there are four members in the jack family which are called as jack 1 jack 2 jack 3 and take 2. the jacks play an important role in mediating signaling pathways when cytokines bind to the cytokine receptors when hematopoietins and interferons bind to their appropriate cytokine receptors they activate a signaling pathway called as the jack stat pathway this pathway is initiated when the cytokine binds to a cytokine receptor which results in the dimerization of the cytokine receptor when the receptor undergoes dimerization the janus kinases or jacks come close to each other and they're able to phosphorylate one another this is called as trans phosphorylation when the jags are phosphorylated they are now active and thus they are able to phosphorylate other proteins the jacks normally phosphorylate the receptor on tyrosine residues and this phosphorylated receptor can now form binding sites for other proteins the phosphorylated tyrosine residues on the receptor are able to form binding sites for a set of proteins called as signal transducer and activator of transcription or stat proteins the stat proteins are transcription factors that are normally present in an inactive state and hence they're unable to function as transcription factors however when stats bind to the phosphorylated tyrosine residues present on the receptor they are able to get phosphorylated by the janus kinases now the stats are able to bind to those phosphotyrosine residues on the receptor through sh2 domains that are part of their structure now once the stats get phosphorylated by the jacks they are able to form dimers and thus they get activated the phosphorylated stat that has formed a dimer is able to bind to different regions of dna and function as a transcription factor now jack stats signaling is activated by hematopoietin cytokines and the signaling results in the regulation of gene expression that play an important role in promoting the growth of immune cells like lymphocytes jugs that signaling has to be tightly regulated in immune cells in fact the constitutive activation of jax that signaling in host cells can cause diseases for example some cancers are associated with aberrant jack stat signaling once the jack stud signaling pathway is activated there has to be mechanisms in the cells to deactivate or silence this jack stat signaling the signaling cascade can be silenced in a variety of ways and one way is by de-phosphorylating the jacks or the cytokine receptor or the stats and by de-phosphorylating any of these components the jack-stack signaling comes to a halt this can be mediated by enzymes like tyrosine phosphatases another way to silence jack stat signaling is by binding to receptors or jacks thereby not allowing the jacks to bind to the receptors or the receptors to bind to jacks and this way the signaling can be terminated there is a group of proteins called as the suppressor of cytokine signaling or sox proteins that are able to bind to the receptors or the jacks and terminate signaling another way to silence the jack stat pathway is to bind to the active stats so that they are unable to transcribe genes another group of proteins called protein inhibitors of activated stat or pious proteins are known to function by this mechanism in order to regulate jack stats signaling interferons are cytokines that are able to bind to type 2 cytokine receptors and these receptors do not have intrinsic kinase activity hence they have kinases associated in their cytoplasmic regions which belong to the jack family thus when interferons bind to their appropriate receptors the jack stat pathway gets activated now the interferons can be categorized into different families which include the type 1 interferons which have interferon alpha and interferon beta as their members interferon gamma belongs to the type 2 interferon family while interferon lambda is often described as the type 3 interferon all these interferons when they bind to their receptors will activate the jack stack pathway the jack stat pathway results in the activation of the stat proteins which get phosphorylated and are able to form dimers in the case of the type 1 interferon signaling pathway this phosphorylated dimerized stats are able to associate with another protein called irf9 and this complex is able to bind to dna to transcribe genes on the other hand in the case of the type 2 interferons the phosphorylated and dimerized stats themselves are able to bind to the promoter of genes to stimulate transcription now whether it is type 1 or type 2 interferons a lot of times the genes that are transcribed are the interferon stimulated genes or isgs interferons play important roles in host defense by activating innate immune cells as well as inducing resistance to viruses they're able to induce resistance to viruses by synthesizing interferon stimulated genes or isgs the isgs have antiviral activity and an example of one isg is ifi tm3 tm3 is known to prevent the fusion of viruses to the endosomes of the host cells which usually helps in the virus to gain entry into the host cell thus by preventing this fusion the host cell does not get infected by the virus another isg is pkr pkr suppresses protein translation in the host cell and this way the virus is unable to synthesize its own viral proteins using the host's protein synthesis machinery another example of an isg is oas now oas activates an endo ribonuclease in the host cell which is able to degrade viral rna thus we can see different ways by which antiviral proteins are being synthesized as a result of interferon signaling with this we come to the end of our talk where we learn about different types of cytokine and chemokine receptors and the signaling pathways that get activated when cytokines are able to bind to the appropriate cytokine receptors we looked at signaling activated by hematopoietins and interferons and finally learned about the outcome of cytokine signaling