Cytokines, Chemokines, and Cell Signaling PDF

1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 agents used for the treatment of many inflammatory conditions and prevention of transplant rejection. Many of these will be covered later in Pharmacology. This i...

1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 agents used for the treatment of many inflammatory conditions and prevention of transplant rejection. Many of these will be covered later in Pharmacology. This is a list of cytokines and chemokines and their main functions as a reference. IL-1β: initiation of inflammatory response, induction of other proinflammatory cytokine synthesis and secretion (IL-1β, TNF-α, IL-6, & CXCL8) as well as other inflammatory mediators (leukotrienes, prostaglandins) and adhesion molecules (endothelial cell activation, i.e., expression of selectins and integrins); fever, synthesis of acute-phase reactants by the liver; CD4 T lymphocyte differentiation into pathologic TH17 cell subset (autoimmune diseases); signals mainly through IL-1R TNF-α: vasodilation, chemotaxis, endothelial activation (endothelial selectin & integrin expression & leukocyte integrin expression in inflammatory bed), transendothelial migration (increased vascular permeability through disruption of adherens junctions, for example), activation of neutrophils and macrophages, fever, increased muscle and fat catabolism (cachexia); signals mainly through TNFR LTα (Lymphotoxin α; TNF family) LTβ (Lymphotoxin β; TNF family): IL-6: fever, synthesis of acute-phase reactants by the liver; leukocyte proliferation; CD4 T lymphocyte differentiation into TH17 cell subset (for responses against extracellular microbes); signals mainly through IL-6R IL-12: activation of NK cells for the synthesis and release of IFN-γ; CD4 T lymphocyte differentiation into TH1 cell subset (for responses against intracellular microbes); activation of Cytotoxic T Lymphocytes (CTLs; cytotoxic CD8 subset); signals mainly through type I cytokine receptors IFN-γ (Type II IFN): activation of macrophage microbicidal functions (M1 macrophages); CD4 T lymphocyte differentiation into TH1 cell subset (for responses against intracellular microbes); isotype-switching to IgG; involved in Type IV hypersensitivity (Delayed-Type Hypersensitivity or DTH); signals mainly through type II cytokine receptors (specifically the IFNγR) IL-2: proliferation of T and B lymphocytes, as well as NK cells; signals mostly through common γ-chain receptors, but also through Toptype I cytokine receptors IL-15: development and proliferation of NK cells and proliferation of T lymphocytes; signals mainly through common γ-chain receptors, but also type I cytokine receptors https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 13/35 1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 IL-4: CD4 T lymphocyte differentiation into TH2 cell subset (for responses against worm infections); isotype-switching to IgE; alternative activation of macrophages (M2 macrophages); involved in Type I hypersensitivity reactions (immediate or allergic & asthma); signals mainly through type I cytokine receptors, but also through common γ-chain receptors IL-5: proliferation and activation of eosinophils; involved in Type I hypersensitivity reactions (immediate or allergic & asthma); signals mainly through type I cytokine receptors, but also through GM-CSF receptors IL-13: increased mucus production by goblet cells; isotype-switching to IgE; alternative activation of macrophages (M2 macrophages); signals mainly through type I cytokine receptors IL-17: increased chemokine production (mainly CXCL8) by macrophages, epithelial cells, fibroblasts, and keratinocytes at the site of infection to attract neutrophils (mainly) and monocytes; increased leukocyte production (neutrophils mainly & monocytes) by the bone marrow (GM-CSF, G-CSF, & M-CSF); signals mainly through the IL-17R IL-22: increased barrier protection and defensin (small cationic proteins capable of destabilizing microbial membranes) production by epithelial cells and neutrophils (& other cells) at the site of infection; signals mainly through type II cytokine receptors IL-23: CD4 T lymphocyte differentiation into pathologic TH17 cell subset (autoimmune diseases); upregulation of TH17 cells; signals mainly through type I cytokine receptors IL-21: B lymphocyte activation and proliferation; inhibition of NK cells and CTLs; signals mainly through type I cytokine receptors, but also through common γ-chain receptors IL-18: induction of antiviral mediators; activation of non-cytotoxic CD8 T lymphocytes; signals mainly through IL-6R IFN-α (Type I IFN): antiviral state (intracellular response); signals mainly through type II cytokine receptors IFN-β (Type I IFN): antiviral state (intracellular response); signals mainly through type II cytokine receptors IFN-l (Type III IFN; IL-28, IL-29): antiviral state (intracellular response); signals mainly through type II cytokine receptors TGF-β: anti-inflammatory; CD4 T lymphocyte differentiation into TH17 cell subset (for responses against extracellular microbes); mainly signals through the TGF-βR Top IL-10: anti-inflammatory; inhibition of IL-12 expression; signals mainly through type II cytokine receptors IL-3 and stem cell factor: hematopoiesis (immature cells); signals mainly through type I cytokine receptors https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 14/35 1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 IL-7: proliferation of NK and T lymphocyte progenitors; maturation of B cells following activation (IL-7 does, however, stimulate some subsets of B cell progenitors); signals mainly through type I cytokine receptors and common γ-chain receptors GM-CSF (granulocyte/macrophage colony stimulating factor): maturation of granulocytes and monocytes; macrophage activation; signals through type I cytokine and GM-CSF receptors G-CSF (granulocyte colony stimulating factor): maturation of granulocytes; signals mainly through type I cytokine receptors M-CSF (macrophage colony stimulating factor): maturation of monocytes; signals mainly through type I cytokine receptors Platelet-activating factor (PAF): involved in inflammation and thrombotic cascades; signals mainly through seven transmembrane G-protein-coupled receptors CXCL8 (IL-8; chemokine): chemotaxis, all leukocytes, but neutrophils especially; CXCL8 signals through CXCR1 and CXCR2, and these receptors signal mainly through seven transmembrane G-protein-coupled receptors CCL3 (MIP-1a or macrophage inflammatory protein 1-α; chemokine): recruitment and activation of leukocytes through binding to the receptors CCR1, CCR4, and CCR5; fever, but mechanism independent from prostaglandins and cyclooxygenase; induce the production of IL1β, IL-6, and TNF-α CCL4 (MIP-1β or macrophage inflammatory protein 1-β; chemokine): recruitment and activation of leukocytes through binding to the receptors CCR1, CCR4, and CCR5; fever, but mechanism independent from prostaglandins and cyclooxygenase; induce the production of IL1β, IL-6, and TNF-α CXCL2 (MIP-2 or macrophage inflammatory protein 2; chemokine): chemotaxis of leukocytes to the site of injury and activation of neutrophils; signals through CXCR1 and CXCR2 CCL20 (MIP-3α: or macrophage inflammatory protein 3-α; chemokine): chemotaxis of activated B cells, memory T cells, and immature dendritic cells in mucosa and skin; migration of dendritic cells and lymphocytes in secondary lymphoid tissue; signals through CCR6 CCL19 (MIP-3β: or macrophage inflammatory protein 3-β; chemokine): chemotaxis of mature dendritic cells to lymph nodes; chemotaxis of naïve T lymphocytes and B lymphocytes to the lymph node; signals through CCR7 Top CCL2 (MCP-1 or monocyte chemoattractant protein 1; chemokine): chemotaxis and infiltration of monocytes, memory T lymphocytes, and NK cells; signals through CCR2 https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 15/35 1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 CXCL10 (IP-10 or interferon-g-inducible protein 10; chemokine): chemotaxis of monocytes and macrophages, T lymphocytes, NK cells, and dendritic cells; T cell adhesion to endothelial cells; angiogenesis; signals through CXCR3 CCL5 (RANTES): T lymphocyte and NK cell chemotaxis; signals mainly through seven transmembrane G-protein-coupled receptors CCL11, CCL24 and CCL26 (eotaxin-1, eotaxin-2, & eotaxin-3 respectively): eosinophil chemotaxis; signal mainly through seven transmembrane G-protein-coupled receptors VEGF-A (vascular endothelial growth factor A): involved in angiogenesis, endothelial cell growth, vascular permeability (inflammation), and chemotaxis; signals through VEGFRs, which are tyrosine kinase receptors  Currently, six families of cytokine receptors are recognized (figure below – upper panel). Of these, you need to know five (these are highlighted in yellow in the figure below): (1) type I cytokine receptor, (2) type II cytokine receptor, (3) TNF receptor family, (4) IL-1 receptor family, and (5) seven transmembrane G-protein-coupled receptor. In addition, some type I cytokine receptors share some receptor subunits. For example, the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 all share at least one subunit, the IL-2 receptor common gamma chain (IL-2Rγc – figure below – lower panel) – this is an important receptor subunit to know, and also important clinically is the fact that the tyrosine kinase (TK) associated with the IL-2Rγc is JAK3; furthermore, the IL-2 and IL-15 receptors share two subunits, the IL-2Rβc and IL-2Rγc. Similarly, some type I cytokine receptors contain other common subunits, e.g., GM-CSF receptor family common β chain (GM-CSF & IL-5) and IL-6 receptor family common gp130 subunit (IL-6, IL-11 & IL-27). Cytokine and chemokine receptor families that you are required to know at this point are highlighted in yellow in the accompanying image titled “Cytokine Receptor Families and Subunit Composition of Cytokine Receptors”; note that the common γ-chain family is a sub-group of the type I cytokine receptor family. You are also required to know compositions of the IL-2, IL-4, IL-7, and IL-15 receptors in the accompanying image titled “Subunit composition of the cytokine receptors containing an IL-2 receptor common γ-chain subunit (IL-2Rγc)”. Top https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 16/35 1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 Cytokine Receptor Families and Subunit Composition of Cytokine Receptors Cytokine receptor families are a diverse group of cell surface proteins essential for transmitting signals in the immune system, regulating inflammation, and maintaining homeostasis in the body. Top https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 17/35 1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 Subunit Composition of Cytokine Receptors Containing an IL-2 Receptor Common ɣchain Subunit (IL-2Rɣc) Cytokine receptors containing the IL-2 receptor common ɣ-chain subunit (IL-2Rɣc) play a pivotal role in the immune system by facilitating signal transduction for various interleukins, contributing to immune cell development, activation, and immune response regulation. Top https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 18/35 1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 Associate the cytokine with its receptor. CD40L IL-1R 7-transmembrane G-protein-coupled receptor CXCL8 Type I cytokine receptor Type II cytokine receptor IFN-γ TNFR IL-1β IL-7  Check  Question 1 Cytokine Receptor CD40L TNFR CXCL8 7-transmembrane G-protein-coupled receptor IFN-γ Type II cytokine receptor IL-1ß IL-1R IL-7 Type 1 cytokine receptor Question 2 A patient with a JAK3 deficiency would present with the same disease as a patient with an IL2RγC deficiency: True (Correct answer) False Top https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 19/35 1/24/24, 1:03 PM Week 2: Fusion Session | Workshop: Cytokines, Chemokines, & Cell Signaling: Hemtlgy Onclgy Infectn Imm - January 2024 Explanation: JAK3 being the TK specifically associated with the IL-2RγC means that a deficiency in either will result in the same outcomes. Click each section below to learn more about each receptor family. This is the receptor family primarily used by the vast majority of cytokines (interleukins & Colony-Stimulating Factors or CSFs) and mainly signals through a JAnus Kinase/Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway. There are four known JAK (JAK1, JAK2, JAK3, & TYK2 – these are all TKs) and seven STAT (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, & STAT6) proteins. The responses elicited by different cytokines depend on the combinations of JAKs and STATs associated with specific cytokine receptor subunits. We will further develop JAK/STAT signaling in a following section. For example, IL-4 signaling mostly yields the activation of STAT6 homodimers which is the transcription factor responsible for turning on IL-4-responsive genes, whereas IL-12 signaling mostly activates STAT4 homodimers which is the transcription factor responsible for turning on IL-12-responsive genes. These and other cytokines can also yield the activation of STAT heterodimers which result in different responses. There are several JAK inhibitors currently approved for treatment (and many more in clinical trials), namely for the treatment of rheumatoid arthritis, atopic dermatitis, psoriatic arthritis, ulcerative colitis, myelofibrosis, COVID-19, ankylosing spondylitis, polycythemia vera, and graft-versus-host disease. This is the main receptor used by interferons (interferons were so named because, upon discovery, they were shown to ‘interfere’ with viral replication in virally-infected cell cultures, and they were also the first cytokines discovered; also, just so you know, IL-10 is technically an interferon, but it acts mostly as an anti-inflammatory mediator…) and this receptor family also primarily signals through JAK/STAT pathways. For example, IFN-γ signals through STAT1 homodimers, whereas IFN-α signals through STAT1/STAT2 heterodimers. This is the primary receptor for TNFs, Top but some TNF receptors (TNFRs) also serve as receptors for other important molecules, such as FasL (CD95L or CD178) and CD40L (CD154). The TNFRs primarily signal through the Nuclear Factor kappa B (NF-kB) pathway, which we will further develop in a later section. https://rossmed.instructure.com/courses/3318/pages/week-2-fusion-session-%7C-workshop-cytokines-chemokines-and-cell-signaling 20/35