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Cytokines and Chemokines Cellular interaction made simple Leo Carr Immunopharmacology March 1, 2006 Cytokine Basics • • Cytokine or immunocytokine is a generic name used to describe a diverse group of soluble proteins and peptides which act as humoral regulators at nano- to- picomolar concentrations Cytokines modulate the functional activities of individual cells and tissues both under normal and pathologic conditions Cytokine Basics • The term cytokine is used to separate this • group of immunomodulatory proteins from other growth factors that modulate nonimmune cells Unfortunately, Growth factors and cytokines both act as cellular survival factors by preventing apoptosis - this fact adds confusion to the understanding and naming of cytokines Cytokine Names • Interleukins - produced exclusively by • • • • • leukocytes Lymphokines - produced by lymphocytes Monokines - produced exclusively by monocytes Interferons - involved in antiviral responses Colony Stimulating Factors - support the growth of cells in semisolid medias Chemokines - promote chemotaxis. Cytokine Basics • • Cytokines behave like classical hormones in that they act at a systemic level, affecting, inflammation, septic shock, acute phase reactions, wound healing, and the neuroimmune network Unlike hormones, cytokines are not produced by specialized cells or in specialized glands - they have no single organ source (this helps clear some of the confusion) Cytokine Activity • Cytokine actions may be characterized as: –Autocrine (self modulating) –Paracrine (modulating cells in the immediate surroundings) –Juxtacrine (modulating through cell membrane signaling) –Retrocrine (modulating to stop host defense) Cytokine Basics • Defining cytokines based only on their • producer cells or target cells is inaccurate The historic cytokine concept of "one producer cell -one cytokine -one target cell" has been falsified for almost every cytokine Cytokine Basics • • • Almost all Cytokines are pleiotropic effectors showing multiple biological activities Also, multiple cytokines often have overlapping activities A single cell frequently interacts with multiple cytokines with seemingly identical responses - cross-talk Cytokine Assays • • The biological activities of cytokines can be measured by a variety of bioassays which may employ factor-dependent cell lines, or antibodies (ELISA) RT-PCR quantitation of cytokines detects the presence of mRNA encoding specific cytokines Soluble - Vs - Membrane • Many Membrane-bound cytokine forms • • have been characterized Some cytokines may also be associated with the extracellular matrix Switching between soluble and membrane bound forms of cytokines may be an important immunoregulatory event Cytokine Regulation • • • Most Cytokines are not stored inside cells (exceptions are, for example TGF-b and PDGF which are stored in platelets) The expression of most Cytokines is strictly regulated - factors are usually produced only by activated cells in response to an induction signal Expression is normally transient and can be regulated at all levels of gene expression Cytokine Action/Timing • A hierarchical order of cytokine actions has • been observed with some early cytokines pre-activating cells so that they then can respond to late-acting cytokines Many cytokines induce the synthesis of novel gene products once they have bound to their respective receptors Cytokine Transport • Cytokine mediators can be transported • • quickly to remote areas of a multicellular organism They can address multiple target cells and can be degraded quickly. Concentration gradients can be used to elicit specific responses These capabilities far exceed the interaction provided by cell-to-cell contacts within a multicellular organism Pre/Postnatal Cytokines • • Cytokines are important mediators involved in embryogenesis and organ development and their activities in these processes may differ from those observed postnatally They also play a key role in neuroimmunological, neuroendocrinological, and neuroregulatory processes Cytokine - Regulation • Cytokines are important positive or negative regulators of mitosis, differentiation, migration,cell survival, apoptosis, and transformation-oncogene Virus Effects • Viral infectious agents exploit the cytokine • repertoire to evade immune responses of the host Virus-encoded factors appear to affect the activities of cytokines in at least four different ways: – by inhibiting the synthesis and release of cytokines from infected cells – by interfering with the interaction between cytokines and their receptors Virus Effects • Virus-encoded factors appear to affect the activities of cytokines in at least four different ways: – by inhibiting signal transmission pathways of cytokines – by synthesizing virus-encoded cytokines that antagonize the effects of host cytokines mediating antiviral processes (viroceptor and virokines) Cytokines In Therapy • • The many specific activities of individual cytokines have been the basis for current concepts of therapeutic intervention particularly, hematopoietic malfunctions and tumor therapy Applications involve the support of chemoand radiotherapy, bone marrow transplantation, and general immunostimulation - adoptive immunotherapy Cytokine Shape/Type • Among the many different cytokines, the Type I cytokines share a similar four ahelical structure and correspondingly, their receptors also share characteristic features that have led to their description as the cytokine receptor superfamily, or Type I cytokine receptors Cytokine Shape/Type • Despite extremely limited amino acid sequence similarities between different Type I cytokines - all Type I cytokines have similar three-dimensional structures Cytokine Type I Subgroups • Type I cytokines can be further divided into • either short-chain or long-chain The short-chain cytokines include: – IL-2, IL-3, IL-4, IL-5, IL-7, IL-9, IL-13, IL-15 – Granulocyte-macrophage colony-stimulating factor (GM-CSF) – Monocyte-CSF (M-CSF), – Stem cell factor (SCF), Cytokine Type I Subgroups • Long-chain cytokines include: – IL-6, IL-11 – Erythropoietin – Thrombopoietin – Leptin – Leukemia inhibitory factor (LIF) – Oncostatin M (OSM) – Ciliary neurotrophic factor (CNTF) – Cardiotrophin-1 (CT-1) – Granulocyte colony-stimulating factor (G-CSF) Cytokine Receptors Cytokine Receptors • • The receptors for five different immunologically important cytokines, IL-2, IL-4, IL-7, IL-9, and IL-15, share the common cytokine receptor g chain, gc (CD132) p.515 in Abbas These cytokines are all short-chain Type I cytokines Cytokines Receptors IL-2 IL-2 Production • Mature IL-2 is a peptide 133 amino acids • • • long Produced mainly by mitogen activated CD4+T-lymphocytes Originally called T-cell growth factor (TCGF) Transformed T-cells and B-cells, leukemia cells,LAK cells (Lymphokine-activated killer cells) and NK-cells also secrete IL-2 IL-2 Actions/Modulation • Secondary signals are required for maximal • • • • expression of IL-2 Resting cells do not produce IL-2 Induces cell cycle progression in resting cells Allows clonal expansion of activated Tlymphocytes Growth/expansion effect is modulated by hormones such as prolactin IL-2 Actions/Modulation • In vitro synthesis of IL-2 is inhibited by • • dexamethasone or CSA Vitamin E can enhance IL-2 production With increasing age, the antigen/mitogenstimulated synthesis of IL-2 (T-cell-mediated immune response) decreases IL-2 Facts • IL-2 damages the blood-brain barrier and • • the integrity of the endothelium of brain vessels IL-2 does not have a saturable transport system across the blood-brain barrier Electrophysiological alterations may cause neuropsychiatric side effects such as fatigue, disorientation, and depression, frequently observed under IL-2 therapy IL-2 Summary • IL-2 important actions: – It can increase immunoglobulin synthesis and Jchain transcription – Proliferation in B cells (with IL-4) – potently augment the cytolytic activity of natural killer (NK) cells – induce the cytolytic activity of lymphokineactivated killer (LAK) cells – Due to its effects on T-cells and B-cells IL-2 is a central regulator of immune response – Passes BBB IL-4 IL-4 Production • IL-4, like IL-2, is produced principally by • activated CD4+ T cells It is also produced by natural killer cells, and by mast cells and basophils IL-4 Actions/Modulation • IL-4 is the major B-cell growth factor • Vital for immunoglobulin class switch IgG to • IgE and inhibits the synthesis of IgM and other IgG subtypes IL-4 induces expression of class II major histocompatibility complex (MHC) molecules on B cells and increases cell surface expression of FceRII (CD23) IL-4 Actions/Modulation • IL-4 can inhibit responses of cells to IL-2 • IL-4 can also exert actions on: – T-cells (proliferation) – Macrophages – Hematopoietic precursor cells – Stromal cells – Fibroblasts – Myelomas (inhibiting IL-6 - myeloma growth factor) IL-7 IL-7 Production • • • IL-7 is not a lymphokine but instead is produced by stromal cells IL-7 is secreted constitutively into bone marrow stroma, and thymic cells Murine and human keratinocytes have been shown also to express and secrete IL-7 IL-7 Actions/Modulation • Its major role is to enhance thymocyte • • growth, survival, and differentiation It also has some activity for the growth of mature T- cells Although important for growth of murine preB cells, it is now clear that human B cells can develop in the absence of IL-7 IL-7 Actions/Modulation • • • IL-7 stimulates the proliferation of pre-B and pro-B-cells without affecting their differentiation IL-7 can replace murine bone marrow stromal cells in supporting the extended growth of both pre-B-cells and pro-B-cells It does not act on mature B-cells IL-9 IL-9 Production • IL-9 was originally described as a murine T- • • cell growth factor. Human and murine IL-9 are 126 amino acids long IL-9 is produced by activated T-cells and supports the growth of T-helper (Th) clones but not CD8+ cytolytic clones In contrast to IL-2, its production is much more delayed, suggesting late/secondary signaling IL-9 Production • IL-9 can be isolated from culture of mitogen- • • or antigen-stimulated T helper cells In primary lymphocyte cultures it is produced predominantly by cells expressing CD4 The synthesis of IL-9 can be induced by calcium ionophores (Ionomycin) IL-9 Actions/Modulation • • • IL-9 stimulates the proliferation of a number of T helper cell clones in the absence of antigens or antigen-presenting cells It does not promote the proliferation of freshly isolated T-cells or cytolytic T-cells The activity as a growth factor seems restricted to a distinct subpopulation of cells or to a particular late activation state IL-15 IL-15 Production • IL-15 is the most recently identified Type I • cytokine Although IL-15 messenger RNA (mRNA) is produced by a range of non-lymphocytic cell types, it is difficult to detect IL-15 protein production IL-15 Actions/Modulation • IL-15 receptors are widely expressed, and it is becoming more clear that IL-15 plays a major role related to NK cell development and cytolytic activity Type I Cytokines • IL-2, IL-4, IL-7, IL-9, and IL-15 collectively exhibit overlapping roles related to T cells, NK cells, B cells, and mast cells, and together would be expected to play vital roles in normal development and function of these cells Break Chemokines • Chemoattractant Cytokines • Small (8-10kd) secreted heparin-binding • Promote recruitment and activation of • leukocytes Can be divided into subclasses by virtue of structural properties Chemokine Subclasses • • • • • Most chemokines have 4 cysteine residues which form disulphide bonds CC class – The first two cysteines are adjacent (example: MCP-1, RANTES) CXC class- The first two cysteines are not adjacent (example: IL-8) C class – Only has 2 cysteines not 4 (example: Lymphotactin) CX3C class – Has 3 amino acids between the first two cysteines and a different N-terminal Chemokine Subclasses Chemokine Function Chemokine Function • Recruitment of inflammatory cells to • • • • infection Provide immune homeostasis Important in host defense against bacteria, parasitic and viral infection Role in wound healing Role in hematopoesis and angiogenesis under study Chemokine Function • Chemokines promote chemotaxis in the direction of highest concentration Chemokine Effects • Chemokines promote shape change in cells • Polymerization and breakdown of actin • Breakdown of lamellipodia (cell anchoring • • arms/legs) Upregulate integrins causing cell adhesion in vascular endothelium Promote cell diapedesis Chemokine Effects Chemokine Signaling 7 transmembrane g-coupled signaling on 3rd loop Chemokine Receptors • Specific receptors bind specific chemokine – CXCR1 binds IL-8 • There are also shared receptors – CCR1 binds MIP-1a,RANTES, MCP-2 and MCP3 • Promiscuous receptors bind any class • Viral encoded receptors – Encoded by cytomegalovirus- CMV U28 binds CC chemokines Chemokine Receptors Chemokines in Disease • MIP-1, and RANTES were discovered to be • HIV suppressor factors CCR2 Ko mice and MCP-1 Ko show reduced atherosclerotic lesions Chemokines in Transplantation • Many chemokines are expressed in • • transplantation (RANTES, MIP-1, IP-10) CXCR3 Ko mice show reduced graft rejection Antibodies to CXCR3 ligands imiprove graft survival Chemokines in Transplantation • Chemokine receptors are differentially expressed on effector T-cells Chemokine/Cytokine Interaction • Allergic reaction Chemokine/Cytokine Interaction • Dermatitis Therapeutic Trials Questions?