Interleukins

Initially investigators believed that interleukins were made chiefly by leukocytes (white blood cells) to act primarily on other leukocytes, and for this reason they named them interleukins, meaning “between leukocytes”.

• In the activation phase of adaptive Ir, they stimulate the growth and differentiation of lymphocytes and in the effector phases of innate and adaptive immunity they activate different effector mechanisms to eliminate microbes and other agents.

• Cytokines proteins secreted by the mononuclear phagocytes were called monokines and those produced by lymphocytes were called lymphokines

Once activated by a complex of antigen plus major histocompatibility complex (MHC) and appropriate costimulatory signals, T lymphocytes release a variety o f biologically active substances collectively referred to as lymphokines.

Interleukins are biologically active glycoproteins derived primarily from activated lymphocytes and macrophages that modulate and regulate immune and inflammatory reactions.

Types are molecularly characterized and assigned numbers are IL-1, IL-2 and so on.

General Properties

Cytokine secretion is brief, self limited event The actions of cytokines are often pleiotropic and redundant Cytokines often influence the synthesis and actions of other cytokines Cytokines action may be local and systemic (autocrine and paracrine) Cytokines initiate their action by binding to specific membrane

receptors on target cells External signals regulate the expression of cytokine receptors and

thus the responsiveness of cells to cytokines The cellular responses to most cytokines consist of changes in gene

expression of new functions and sometimes in the proliferation of target cells

Cellular responses to cytokines are tightly regulated and feedback inhibitory mechanisms exist to turn down these responses

• Based on their principal biologic actions.– Mediators and regulators of innate immunity– Mediators and regulators of adaptive immunity– Stimulators of hematopoiesis

Cytokines that mediate and regulate Innate immunity

TNFIL 1ChemokinesIL 12Type I interferonsIL 10IL 6IL 15IL 18IL 23IL 27

Cytokines that mediate and regulate Adaptive immunity

IL 2 IL 4 IL 5 IL 13 Interferon ɤ Transforming growth factor β LMPHOTOXIN IL 17 IL 21

• Cytokines that stimulate Hematopoiesis– Stem cell factor– IL 7– IL 3– GM – CSF

• Granulocyte stimulating factor• Macrocyte colony stimulating factor

– Erythropoietin– IL 9– IL 11

Interleukin receptorAn interleukin receptor is a cytokine receptor

for interleukins.• Types• There are two main families of Interleukin

receptors, type 1 and type 2 cytokine receptors.• Type 1• Type 1 interleukin receptors include:• Interleukin-2,3,4,5,6,7,9,11,12,13,15,21,23,27

types.

• Type 2• Type 2 interleukin receptors include:• Interleukin-10 receptor20,22,28• Other• Interleukin-1 receptor and interleukin-18

receptor belong to the immunoglobulin super family

• interleukin -8 receptor, RANTES receptors belong to the chemokine receptor family.

Type I cytokine receptors are trans membrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands.

These receptors are also known under the name hemopoietin  receptors, and share a common amino acid motif (WSXWS) in the extracellular portion adjacent to the cell membrane.

Members of the type I cytokine receptor family comprise different chains,

some of which are involved in ligand/cytokine interaction and others that are involved in signal transduction.

Signal transduction chains The signal transducing chains are often shared

between different receptors within this receptor family.

The IL-2 receptor common gamma chain is shared between: IL-2 4,7,9,13,15 receptor

The common beta chain is shared between the following type I cytokine receptors: IL-3 ,5 receptor

General model of cytokine receptors for interleukin and interferon types of cytokines.See figure 12-6 (b) and (c) p. 308, for interleukin (“hematopoietin”) and interferon class of cytokines

STAT = signal transducers and activators of transcription.See Table 12-2, p. 313 for STAT family of transcription factors associated with different cytokines of the interleukin and interferon series

• Type II cytokine receptors are transmembrane proteins that are expressed on the surface of certain cells, which bind and respond to a select group of cytokines.

• Thesereceptors are similar to type I cytokine receptors except they do not possess the signature sequence WSXWS that is characteristic of type I receptors.

• Typically type II cytokine receptors are heterodimers or multimers with a high and a low affinity component.s

• +3

• IL-1 was first described as a protein inducing fever and was called human leukocytic pyrogen

• 11 members of the IL-1 family exist

• Genes for IL-1a, IL-1b, and IL-1Ra are closely associated in the region of 2q12-q13 of human chromosome 2.

• IL-1R belongs to the Toll–IL-1—receptor (TIR) superfamily, which is defined by an intracellular TIR domain that initiates the signaling cascade.

• TIR receptors can be divided into 2 subgroups regarding the extracellular domains. One group contains a leucine-rich repeat motif, and the other group is characterized by an immunoglobulin-like domain.

• IL-1 is expressed by many cells including macrophages, monocytes, lymphocytes, keratinocytes, microglia, megakaryocytes, neutrophils, fibroblasts, and synovial lining cells.

• IL-1RI is expressed on all cells responding to IL-1a and b, predominantly on T cells, fibroblasts, epithelial cells, and endothelial cells

• The principal function of IL 1 is as a mediator of the host inflammatory response to infections and other stimuli

• IL-1a and b, produced by activated macrophages and monocytes, are one of the key players in the innate immune response.

They play an important role in coordination of local and systemic inflammation by causing inflammation and inducing the expression of other proinflammatory genes like COX type II, inducible nitric oxide synthase, and other cytokines or chemokines

IL-1b plays a major role in a wide range of autoimmune and inflammatory diseases by initiating and potentiating inflammatory responses.

• IL-1b induces synthesis of chemokines, including IL-8, which is a potent neutrophil chemo attractant

• Neutrophils can enhance the inflammation by inducing proinflammatory cytokines and release of neutrophil granule enzymes, which are involved in tissue damage

• IL-1Ra neutralizes the effects of IL-1. Complete inhibition of IL-1 requires 10-fold to 100-fold molar excess of IL-1Ra over IL-1.

• The fact that IL-1Ra gene deficiency causes autoimmunity and joint-specific inflammation suggests that the balance between IL-1 and IL-1Ra is important in maintaining the normal physiology of the joints and homeostasis of the immune system

• Low concentration: functions as a mediator of local inflammation

• At high concentrations: enters the blood stream and exerts enocrine effects—induces fever and also neutrophil and platelet production by the bone marrow

IL 2

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

Target cells of IL-2 include CD4+CD8+ T cells, NK cells, and B cells.

The IL-2R consists of 3 subunits, the ligand-specific a-chain IL-2Ra (CD25, originally called Tac for T activation); the b-chain IL-2Rb (CD122), which is also part of the IL-15 receptor complex; and the common gc (CD132), which is shared by IL-4, IL-7, IL-9, IL-15, and IL-21

Actions and modulations

Induces cell cycle progression in resting cells Allows clonal expansion of activated T-

lymphocytes Growth/expansion effect is modulated by

hormones such as prolactin 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

IL 3• It is also known as multilineage colony stimulating factor (multi – CSF)

• IL-3, IL-5, and GM-CSF also share the common receptor subunit b-chain (CD131), resulting in partially overlapping functions of these hematopoietic cytokines.

• IL-3 is expressed by T cells, macrophages, stromal cells, NK cells, mast cells, and eosinophils, and its transcription is regulated by 2 nuclear factor of activated T cells-dependent enhancers that have distinct tissue-specific activity

• IL-3 is a multilineage hematopoietic growth factor, acting on early stages of hematopoiesis rather than on late differentiation and maturation processes

• In combination with erythropoietin, IL-3 induces erythroid lineages, whereas it synergizes with GM-CSF or G-CSF to induce the granulocyte-macrophage lineage.

• IL-3 together with TNF-a leads to short-term proliferation of CD34+ progenitor cells and the differentiation of DCs and Langerhans cells.

• Besides its function as a hematopoietic growth factor, IL-3 is responsible for the activation and the survival of different mature cell types, including basophils.

• IL-3 plays a role in allergic diseases by preventing the apoptosis of basophils

IL 4 • IL 4 is the major stimulus for the production of IgE antibodies and for the

development of Th2 cells from naïve CD4+ helper T cells

• The principal sources are CD4+ T lymphocytes of the TH2 subset as well as activated mast cells

• IL 4 is the principal cytokine that stimulates B cell Ig heavy chain class switching to the IgE isotype

• It stimulates the development of TH2 cells from naïve CD4+ T cells and functions as an autocrine growth factor for differentiated TH2 cells

• together with IL 13 contributes to macrophage activation which promotes the phagocytosis of microbes

IL 5• IL 5 is an activator of eosinophils and serves as a

link between T cell activation and eosinophillic inflammation

• The major action of IL 5 are to activate mature eosinophils and stimulate the growth and differentiation of eosinophils

• Eosinophils express Fc receptors specific for IgA and IgG antibodies and are thereby able to bind to microbes

IL 6• Alternative names are IFN-b2 (IFNB2), B-cell differentiation factor,

BSF2, hepatocyte stimulatory factor, and hybridoma growth factor.

• IL-6 is produced after stimulation by many different cells: T cells, B cells, granulocytes, smooth muscle cells, eosinophils, chondrocytes, osteoblasts, mast cells, glia cells, and keratinocytes.

• Endothelial cells, fibroblasts, and monocytes/macrophages triggered by various stimuli during systemic inflammation are the main source of this cytokine

• IL-6 is involved in a broad spectrum of biological activities, in humoral as well as in cellular defense, and acts on various target cells.

• Regulation of T-cell proliferation and differentiation as well as in the induction of B cells to produce IgM, IgG, and IgA

• A deregulated production of IL-6 affects thepathogenesis of several autoimmune and inflammatory diseases.

IL 7

• IL-7, also known as pre–B-cell growth factor and lymphopoietin- 1, was originally derived from bone marrow stromal cells and described as a mediator that alone could support the growth of Bcell progenitors

• The IL-7R is present on most T cells, progenitors of B cells, and bone marrow macrophages

• IL-7 is a tissue-derived cytokine. It is produced by multiple stromal tissues, including epithelial cells in thymus and bone marrow.

• Additional sites of IL-7 production include intestinal epithelium, keratinocytes, fetal liver, adult liver, DCs, follicular DCs, B cells, and monocytes/macrophages

• IL-7 is required for the survival of naive T-cell populations and contributes to homeostatic cycling of naive and memory cells.

• IL-7 is required for the survival of naive T-cell populations and contributes to homeostatic cycling of naive and memory cells.

• It stimulates the proliferation of thymocytes and is therefore an important differentiation factor for functionally different subpopulations of T cells.

• IL-7 and its receptor are linked to the development of autoimmune diseases

– IL-7 is capable in vivo of causing CD4+ T-cell–dependent destruction of tumor cells and shows a potential contribution to allergen-induced eosinophilic airway inflammation in asthma

IL 8• A wide variety of different cells such as monocytes and macrophages,

neutrophils, lymphocytes, endothelial and epithelial cells, fibroblasts, keratinocytes, synovial cells, chondrocytes, hepatocytes, and smooth muscle and skeletal muscle cells as well as several tumor cell types produce IL-8.

• The major effector function of IL-8 is the recruitment of neutrophils to the site of infection or injury

• Besides neutrophils, IL-8 attracts NK cells, T cells, basophils, and GM-CSF or IL-3–primed eosinophils.

• In the presence of IL-3, IL-8 activates basophils to release leukotrienes and histamine. Thus, IL-8 plays an important role in the innate immunity, providing a first line of defense against invading pathogens

• In addition to its chemokine function, IL-8 stimulates the release of hematopoietic progenitor cells from the bone marrow into the peripheral blood

• There is no direct importance of IL-8 described in TH2-mediated allergic diseases. However, repeated injections of IL-8 lead to neutrophil accumulation in the lung and joints, resulting in pulmonary inflammation and cartilage damage.

IL 9• The main sources of IL-9 are TH2 cells and the recently

discovered TH9 cells

• To a lesser extent, mast cells and eosinophils have been shown to secrete IL-9

• IL-9 is a multifunctional cytokine. It is a potent growth factor for T cells and mast cells, promotes proliferation of CD8+ T cells, and inhibits cytokine production of TH1 cells

• IL-9 is involved in TH2 inflammatory reactions, promotes the production of IL-4–induced IgE, induces chemokine and mucus secretion by bronchial epithelial cells, and leads to mast cell proliferation

IL 10

• The IL-10 gene maps to chromosome 1 (1q31-32) in human• In human beings, IL-10 is mainly produced by monocytes, T cells

(mainly Treg cells), B cells, macrophages, and DCs

• IL-10 is a key regulator of the inflammatory response. Its immunosuppressive effects protect the host from exaggerated inflammatory responses to microbial infections as well as autoimmune diseases

• IL-10 inhibits cytokine production and proliferation of CD4+ T cells mainly indirectly through its effects on APCs

• IL-10 appears to have a protective role in several autoimmune diseases such as diabetes mellitus.

• IL-9 is important in the protection against helminth infections

It was first isolated from bone marrow–derived stromal cells in 1990 The human IL-11 gene is located on the long arm of chromosome 19

(19q13.3-13.4) and consists of 5 exons and 4 introns.

IL-11 is produced by a variety of stromal cells including fibroblast, epithelial cells, endothelial cells, vascular smooth muscle cells, synoviocytes, osteoblasts, and several tumor cell lines

IL-11 increases peripheral platelet counts and was shown to enhance T-cell–dependent secretion of immunoglobulins by B cells

Produced by activated inflammatory cells (eg, monocytes, macrophages, neutrophils, microglia, and DCs), and to a lesser extent B cells

IL-12–activated cells expressed increased levels of transcripts for many genes involved in host defense, including IFN-γ

By inducing IFN- γ production from NK cells and T cells, IL-12 indirectly activates the antimicrobial, antiparasitic, and antitumor activity of phagocytotic cells and promotes cytolytic activity of NK cells and lymphokine-activated killer cells

General Properties

Cytokines are the family of proteins that mediate many of the responses of innate and adaptive immunity

They mediate their action by binding with high affinity to receptors which belong to a limited number of structural families

The cytokines that mediate innate immunity are produced mainly by activated macrophages

The cytokines that mediate and regulate adaptive immune responses are produced mainly by antigen stimulated T lymphocytes

Excessive production or actions of cytokines can lead to pathological consequences

T h a n k y o u