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A

Amphiregulin

Amphiregulin is a glycoprotein member of the epidermal growth factor (EGF) family of proteins. The carboxy-terminal amino acid residues of amphiregulin, positions 46-84, share much sequence homology with the EGF family of proteins. The actions of amphiregulin are wide ranging including the stimulation of proliferation of certain tumour cell lines, Fibroblasts and various other normal cells. These actions are mediated by binding to EGF receptors possessing intrinsic tyrosine kinase activity.

Angiogenin

Angiogenin is a 14.4 kDa protein belonging to a family of proteins called the RNAse superfamily. Angiogenin acts as a potent inducer of blood vessel formation and is known to possess ribonuclease activity. If the ribonuclease activity is blocked the angiogenic properties of angiogenin also appear to be inhibited. Angiogenin mRNA has been identified in a wide range of cell types.

Apolipoprotein E (APO-E)

APO-E is a plasma protein involved in many functions including lipid transport, tissue repair and the regulation of cellular growth and proliferation. There are three major isoforms of APO-E encoded by either the epsilon 2, 3 or 4 alleles (APO-E2, APO-E3, APO-E4). APO-E3 is the most common variant. There is much interest in the APO-E4 variant as it may be implicated in Alzheimer's disease. Other APO-E polymorphisms have been implicated in disorders of lipid metabolism and heart disease.

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B

Betacellulin

Betacellulin is a member of the epidermal growth factor (EGF) family, which acts as a protent mitogen for retinal pigment epithelial cells and vascular smooth muscle cells. Betacellulin is synthesised as a transmembrane protein. Proteolytic cleavage of the extracellular domain results in the release of the biologically active mature form of the protein. The EGF receptor appears to be the primary receptor for betacellulin.

Brain Derived Neurotrophic Factor (BDNF)

BDNF is a neurotrophic factor found widely expressed in the adult central nervous system. Predominant expression is in the hippocampus, cortex and synapses of basal forebrain. Although BDNF can also be expressed in muscles. BDNF shares sequence homology with nerve growth factor (NGF) and neurotrophin-3 (NT-3). The receptor for BDNF (trkB) belongs to the tyrosine kinase family of receptors.

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C

C-10

C-10, also known as SCY A6, is amember of the C-C family of chemokines related to MIP-1. This chemokine has only been described in mice and no human homologue is known at present. C-10 is expressed in mouse bone marrow cultures following stimulation with GM-CSF and is also found in macrophages, T lymphocytes and some myeloid cell lines.

Ciliary Neurotrophic Factor (CNTF)

CNTF is a neurotrophin of approximately 24 kDa located predominantly in peripheral nerve tissues. The main sources of CNTF appear to be myelin-associated Schwann cells in peripheral nerves and astrocytes in the central nervous system. CNTF, together with factors, may be involved in the maintenance and regeneration of neurons.

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E

ENA-78

Human ENA-78 is an 8 kDa protein belonging to the C-X-C chemokine sub-family. Various human epithelial cell lines, platelets, monocytes and endothelial cells produce this chemokine which is a potent chemoattractant of neutrophils. In addition to its chemotactic activity, ENA-78 plays an important role in neutrophil activation.

Eotaxin and Eotaxin 2

The C-C chemokine eotaxin is a potent eosinophil chemoattractant involved primarily in the recruitment of eosinophils in the blood to sites of allergic inflammation. Human eotaxin is an 8.4 kDa polypeptide belonging to the platelet factor 4 (PF4) family of chemokines. Cells producing eotaxin include eosinophils, various epithelial cells, lymphocytes and macrophages. The receptor for human eotaxin is a 41 kDa G-protein-couples receptor named CCR3 expressed exclusively by eosinophils. Eotaxin 2, also a C-C chemokine, is functionally similar to eotaxin (induces chemotaxis of eosinophils and basophils). However, despite such functional similarity. There is low amino acid identity between eotaxin and eotaxin 2.

Erythropoietin (EPO)

EPO is a glycoprotein of between 34 and 37 kDa responsible for the regulation of growth and differentiation of erythroid precursor cells and, consequently, for the maintenance of physiological levels of erythrocytes in the bloodstream. EPO is primarily produced in the kidney, although approximately 10-15% of EPO production results from hepatocyte and Kuffer cell production in the liver.

Epidermal growth factor (EGF)

EGF is a 6.4 protein which acts as a potent mitogen for various cells of endodermal, ectodermal and mesodermal origin. Many proteins have been classified as members of the EGF family based on regions of shared sequence homology and the presence of conserved EGF cysteine residues (known as EGF-like repeats). The biological activities of EGF are wide ranging and mediated through a transmembrane receptor designated HER-1. The proliferative effects of EGF are important for the promotion of wound healing and organogenesis.

Exodus and Exodus 2

Eodus (now known as exodus 1) and exodus 2 are members of the C-C chemokine family expressed mainly by lymphocytes and monocytes. Expression of exodus can be upreguhated by TNF-a and LPS. Exodus 1 shares approximately 28% homology with MIP-1a and RANTES, and is identical to LARC and MIP-3a. This chemokine promotes the chemotaxis of peripheral blood mononuclear cells. Exodus 2 stimulates chemotaxis of T lymphocytes and plays a role in the inhibition of haematopoiesis.

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F

Fibroblast Growth Factor (FGF)

The fibroblast growth factors, FGFs, comprise a large family of 16-18 kDa structurally and functionally related proteins involved in the rehulation of a wide range of responses depending on the target cell. The functions of FGFs are mediated via transmembrane protein tyrosine kinase receptors and heparin-like molecules appear to be required for FGF-stimulated biological responses. Due to the high affinity of FGFs for heparin, these factors are sometimes known as heparin-binding growth factors. FGFs are important in the regulation of normal growth and differentiation of epithelial, mesenchymal and neuroectodermal cell types.

FLT-3 Ligand

FLT-3 ligand is a 17 kDa polypeptide that stimulates the proliferation of early haemaopoietic cells. This cytokine belongs to a larger family of factors, of which other members include steel factor and colony stimulating factor 1. FLT-3 ligand acts synergistically with other cytokines such as IL-3, G-CSF, GM-CSF, and M-CSF to exert its proliferative effects which are mediated via tyrosine kinase receptors.

Fractalkine

Fractalkine differs from other chemokines in that it contains a different cysteine motif to those chemokines belonging to the C-X-C, C-C or C sub-groups. This recentoy discovered cysteine motif is known as CX3C (C-X-X-X-C). The chemokine domain of fractalkine is part of a much larger protein of 373 amino acids. This larger protein comprises the 76 amino acid chemokine domain at the amino terminus attached to a mucin-like domain. Fractalkine exists in both a membrane-anchored form and a shed 95 kDa secreted form. The membrane-anchoredform is thought to be expressed on the surface of activaed endothelial cells. The soluble form is a potent chemoattractant for T cells and monocytes.

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G

Glial Derived Neurotrophic Factor (GDNF)

GDNF is a glial cell line-derived neurotrophic factor belonging to the transforming growth factor beta (TGF-b) superfamily. This neyrotrophin is thought to be involved in the survival of neuron populations in the central and peripheral nervous systems.

Granulocyte Colony Stimulating Factor (G-CSF)

G-CSF is a glycoprotein colony stimulating factor of approximately 19 kDa released from activated monocytes, macrophages and neutrophils. Other cells known to produce G-CSF include stromal cells, fibroblasts and endothelial cells. Various tumour cell lines also express G-CSF. Human G-CSF is primarily involved in the proliferation and differentiation of haematopoietic progenitor cells of the neutrophil/granulocyte lineage.

Granulocyte Macrophage Colony Stimulating Factor (GM-CSF)

GM-CSF is a glycoprotein cytokine produced by many different cell types. Macrophages release GM-CSF in response to antigen or mitogen activation, and its release from endothelial cells and fibroblasts may be induced by cytokines such as IL-1, IL-2, TNF-a, TNF-b and IFN-g. The major activities of GM-CSF include the survival, proliferation and differentiation of granulocyte-macrophage cell populations.

GRO

Human GRO is a member of the C-X-C family of chemokines produced predominantly by activated monocytes. Three GRO genes have been identified (GRO-a, GRO-b and GRO-g), each encoding a different protein. The protein encoded by GRO-a is known as MGSA (melanoma growth stimulating activator). GRO-b encodes a protein identical to MIP-2a and GRO-g a protein edentical to MIP-2b. The three genes share approximately 90% sequence homology. Inflammatory cytokines such as TNF, IL-1 and IL-6 induce the expression of GRO. GRO-a induces a number of changes in neutrophils including a transient increase in cytoplasmic calcium concentration, degranulation and a weak respiratory burst. GRO protein appears to be functionally related to IL-8 and binds to the same receptor, CCR1.

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H

Hepatocyte Growth Factor (HGF)

HGF is a glycoprotein growth factor involved in the regulation of hepatocyte proliferation. This growth factor is produced predominantly in the liver and pancreas and may also be present in platelets, kidney, human serum and placenta, HGF released from Kupffer cells and sinusoidal endothelial cells of the liver is thought to play an important role in the regeneration of liver tissue following liver damage.

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I

Insulin-Like Growth Factor (IGF)

There are two recognised forms of IGF known as IGF-I and IGF-II. These growth factors share approximately 67% sequence homology and are known as insulin-like growth factors due to their homology (approximately 47%) and certain effects similar to the hormone insulin. The effects of IGFs are mediated through IGF receptors and secreted IGF binding proteins (IGFBPs). The IGFs display a diverse range of effects on embryonic and foetal growth and development. These growth factors are also important as growth modulators in adult tissue differentiation, cellular proliferation and various cancers.

Interferon Alpha (IFN-a)

Many sub-types of IFN-a have been identified varying in molecular mass of between approximately 19 and 29 kDa. IFN-a is produced by various cell types including monocytes and macrophages, fibroblasts and lymphoblastoid cells. The effects of IFN-a are wide ranging and include potent anti-viral and anti-parasitic activity. In addition, IFN-a has and proliferative effects on certain tumour cells.

Interferon Beta (IFN-b)

IFN-b is a glycoprotein of approximately 20 kDa belonging to the type I family of interferons. This interferon is produced by fibroblasts and certain epithelial cells in response to stimuli including viruses, other microorganisms and cytokines such as TNF and IL-1. IFN-b enhances the expression of HLA class I molecules, but inhibits the expression of HLA class II molecules stimulated by IFN-g. Other activities of IFN-b include the activation of NK cells and an increase in synthesis of the expression of the low affinity IgE receptor (CD23).

Interferon gamma (IFN-g)

IFN-g is produced by T cells and NK cells in response to antigen or mitogen activation. This glycoprotein cytokine exhibits potent IFN-g anti-viral activity and acts synergistically with other cytokines to exert its wides-ranging effects. IFN-g is capable of enhancing the anti-viral effects of IFN-a and IFN-b and can also increase the cytotoxic effects of TNF-a. Other effects of IFN-g include the induction of MHC class II antigens, macrophage activation, increased immunoglobulin production from B cells and enhanced NK cell activity.

Interleukin 1 (IL-1a and IL-1b)

Two forms of IL-1, known as IL-1a and IL-1b, have been identifies which are the protein products of two separate genes. Both IL-1a and IL-1b are synthesised as larger precursor proteins that undergo proteolytic cleavage by a numberof proteases to produce the mature proteins. Many cell types produce IL-1a and IL-1b and the effects of IL-1 cytokines are numerous. IL-1s are important factors in the inflammatory response and act as pyrogens by inducing the production of prostaglandins in the hypothalamus.

Interleukin 1 Receptor Antagonist (IL-1ra)

IL-1ra is a glycoprotein of between 17 and 25 kDa that acts to inhibit the activities of the inflammatory cykines IL-1a and IL-1b. Two splice variants of IL-1ra have been described, a secreted form known as sIL-1ra and an intracellular form known as ICIL-ra. sIL-1ra is secreted from hepatocytes, monocytes, neutrophils and macrophages. ICIL-1ra is mainly produced by keratinocytes, epithelial cells, fibroblasts and macrophages. When bound to IL-1 receptors (both type I and type II receptors), IL-1ra inhibits the binding of IL-1a and IL-1b, but does not appear to demonstrate any biological activity. Because of its inhibitory action on both forms of IL-1, IL-1ra may be implicated in regulating the severity of inflammatory responses. In addition to its role in inhibiting the production of IL-1a and IL-1b, IL-1ra inhibits the expression of other proteins such as IL-2, IL-2 receptors and prostaglandin E2.

Interleukin 2 (IL-2)

Human IL-2 is a polypeptide of approximately 15.5 kDa secreted mainly by antigen or mitogen activated TH1 cells. The biological activities of IL-2 are mediated by a receptor that is almost exclusively expressed on activated T cells but not on resting cells. The binding of IL-2 to its receptor can result in a number of effects, including the induction of proliferation of TH and TC cells and the stimulation of T cells to produce other cytokines such as IFN-g and IL-4, IL-2 can also affect non-T cell types such as B cells, NK cells and macrophages.

Interleukin 3 (IL-3)

Human IL-3 is an early acting haematopoietic growth factor involved in the support of proliferation and differentiation of almost all types of haematopoietic progenitor cells. IL-3 is produced mainly by antigen or mitogen stimulated T dells and acts on a variety of target cells. Consequently, IL-3 performs a wide range of functions both in the haematopoietic and immune systems. IL-3 stimulates colony formation of megakaryocytes, neutrophils and granulocytes from bone marrow culture. In addition, IL-3 is involved in the regulation of T cell growth, macrophage proliferation and differentiation and IgG secretion.

Interleukin 4 (IL-4)

Human IL-4 is a cytokine produced predominantly by activated CD4- TH2 cells and is involved in the proliferation and differentiation of activated B cells. IL-4 increases the expression of MHC class II antigens and IgE receptors on resting B cells. On activated B cells, IL-4 increases the wxpression of IgG1 and IgE. IL-4, as well as acting on B cells, affects a number of other cells including granulocyres, fibroblasts, endothelial cells and certain thymocytes. The biological effects of IL-4 are numerous and many are as a result of indirect action whereby IL-4 stimulates various cell types to produce other cytokines.

Interleukin 5 (IL-5)

IL-5 is a cytokine produced predominantly by T cells and is responsible for the growth and differentiation of eosinophils. This cytokine, due to its roles in the production, activation and localisation of eosinophils, has been implicated in a range of allergic conditions. IL-5 also acts on other cell types, for example, by inducing the proliferation of activated B cells and their subsequent differentiation and by inducing cytotoxic T cell production from thymocytes.

Interleukin 6 (IL-6)

Human IL-6 is a glycoprotein of between 21 and 28 kDa produced mainly by activated monocytes and macrophages although many other cell types produce this cytokine following stimulation. IL-6 is a multifunctional cytokine that influences antigen-specific immune reactions and inflammatory reactions. IL-6 induces B cell differentiation and immunoglobulin secretion, T cell growth and cytotoxic T cell differentiation, and induces the production of hepatic acute phase proteins during the inflammatory response. IL-6 seems to act on very early haematopoietic progenitor cells, possibly even stem cells.

Interleukin 7 (IL-7)

Human IL-7 was originally identified as a factor secreted by bone marrow stromal cells. Thymic cells and keratinocytes have also been shown to produce IL-7 is a 17.4 kDa cytokine exhibiting many biological activities, including the regulation of B cell development and maturation, the stimulation and proliferation of early and mature activated T cells and the induction of pro-inflammatory cytokine production (such as IL-1, IL-6 and MIP) from monocytes. IL-7 appears also to have inhibitory activity by down-regulating the expression of TGF-b from macrophages.

Interleukin 8 (IL-8)

IL-8 is a protein of between 8 and 9 kDa belonging to the C-X-C family of chemokines. This chemokine is initially synthesised as a 99 amino acid protein precursor. Proteolytic cleavage of the precursor cal result in N-terminal variants of IL-8 (69, 72, 77 and 79 amino acid variants). IL-8 is a potent chemoattractant for neutrophils, T cells and basophils. In addition, IL-8 inhibits adhesion of leucocytes to endothelial cells demonstrating a role as an anti-inflammatory factor and plays a role in the promotion of angiogenesis.

Interleukin 9 (IL-9)

IL-9 is a cytokine of approximately 14 kDa produced predominantly by TH2 cells. IL-9 is a multifunctional cytokine and was originally designated T cell growth factor, however, its role in T cell responses is still not fully understood. This cytokine is thought to enhance the survival of T cell lines, to enhance the production of IgE, IgG and IgM from stimulated B lymphocytes and to act in a synergistic fashion with other cytokines such as EPO to support the development of haematopoietic progenitor cells.

Interleukin 10 (IL-10)

IL-10 is a homodimeric protein produced by activated T cells, activated monocytes, mast cells and some B cell lymphomas. Human IL-10 is closely related to the product of the Epstein Barr virus BCRF-1 gene, sharing approximately 84% sequence homology with this gene product. IL-10 is also known as cytokine synthesis inhibitory factor and performs many functions, including the inhibition of pro-inflammatory cytokines from activated monocyted and macrophages, and the promotion of B cell proliferation and immunoglibulin secretion.

Interleukin 11 (IL-11)

IL-11 is a non-glycosylated protein of approximately 23 kDa. This cytokine is produced is produced predominantly by stromal cells. In vitro and in vivo studies have shown IL-11 to possess a broad spectrum of activities. IL-11 induced many aspects of haematopoiesis and plays an important role in the production of acute phase proteins from hepatocytes. As well as its stimulatory effects, IL-11 has been reported to have inhivit the production of adipocytes, and also plays an inhibitory role in macrophage cytokine production and apoptosis.

Interleukin 12 (IL-12)

IL-12 is a 70 kDa glycoprotein heterodimer consisting of a 40 kDa sub-unit (p40) and a 35 kDa sub-unit (p35) linked by disulphide bonds. This cytokine is produced by activated peripheral lyphocytes (mainly B cells) and is an important activator of CD56+ NK cells. Other activities of IL-12 include the stimulation of IFN-g, TNF-a and IL-2 from TH1 cells, the inhibition of cytokines such as IL-4, IL-5 and IL-10 from TH2 cells and a synergistic role with IL-2 in the promotion of LAK cell production. IL-12 is also thought to be involved in the inhibition of IgE synthesis.

Interleukin 13 (IL-13)

IL-13 is a cytokine produced by different T cell sub-sets (mainly by activated TH2 cells). This cytokine exhibits many of the biological activities of IL-4 probably due to shared components of the IL-13 and IL-4 receptors involved in signal transduction. One example of shared IL-4 and IL-13 activity is that both cytokines can induce an immunoglobulin isotype switch to IgE in B cells. The differentiation of B cells can also be induced by IL-13. Research has shown IL-13 to decrease macrophage activity thus resulting in a reduction in the release of macrophage derived pro-inflammatory cytokines and chemokines. Other functions of IL-13 include the induction of monocyte differentiation and an increase in activity of LAK cells.

Interleukin 15 (IL-15)

IL-15 is a cytokine of between 14 and 15 kDa produced by various cell types including activated monocytes and macrophages. Although IL-2 and IL-15 share little sequence homology, some of the biological activities of IL-15 are similar to those of IL-2 probably due to the fact that IL-15 can bind to the b and g chains of the IL-2 receptor. Biological activites of IL-15 include the stimulation of growth and differentiation of B and T cells, a role in NK cell proliferation, maturation and cytokine production and the induction of mast cell proliferation.

Interleukin 16 (IL-16)

IL-16 is a cytokine produced mainly by CD8+ T cells in response to histamine stimulation. This cytokine acts as a potent chemoattractant for CD4+ T cells, eosinophils, and to a lesser degree, monocytes. IL-16 is also produced by eosinophils and may gave an autoregulatory effect on these cellls. The activities of IL-16 appear to be mediated through CD4. A role for IL-16 in the suppression of HIV infection has been postulated as it is thought that this cytokine, through its interaction with CD4, can block attachment of HIV. In addition, IL-16 induces T lymphocyte expression of the IL-2 receptor.

Interleukin 17 (IL-17)

IL-17 is a cytokine produced by activated T cells. The physiological roles of IL-17 are not yet fully defined although it is known that IL-17 induces the expression of intracellular cell adhesion molecule 1 (ICAM-1) in human fibroblasts. IL-17 also stimulates the secretion of other cytokines such as IL-6, MCP-1, G-CSF, and induces prostaglandin E2 synthesis from cells including fibroblasts, epithelial and endothelial cells.

Interleukin 18 (IL-18)

IL-18 is a novel cytokine originally described as an IFN-g inducing factor (IGIF), due to its ability to induce IFN-g production from TH1 NK cells. Recent studies however, have suggested additional actions of this cytokine. IL-18 may enhance expression of Fas ligand, NK cells activity and GM-CSF production. In addition, this cytokine can activate nuclear factor kappa B (NF-kB) and induce the production of C-C and C-X-C chemokines.

Interferon-Inducible Protein -10 (IP-10)

IP-10 is a member of the C-X-C family of chemokines produced by a variety of cell types in response to IFN-g. Cell types expressing IP-10 include endothelial cells, fibroblasts, monocytes and keratinocytes, TNF-a and bacterial lipopolysaccharides can also induce the expression of IP-10. This chemokine is a potent chemoattractant for activated T lymphocytes and appears to inhibit angiogenesis.

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K

Keratinocyte Growth Factor (KGF)

KGF is a member of the FGF growth factor family of mitogens. In contrast to FGFs which act on a variety of cell types influencing cellular perliferation and differentiation, KGF appears to act specifically on epithelial cells. KGF has been identified as an important factor influencing the growth promotion of skin keratinocytes. It follows therefore, that KGF plays a vital role in wound healing following skin damage, KGF appears to be involved in repair processes of various other tissues and organs through its action on epithelial cells.

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L

Leptin

Leptin is a protein of 167 amino acids encoded by the ob gene. This protein is produced by adipose tissue and is involved in the maintenance of body weight homeostasis and energy balance. The effects of leptin are mediated via the leptin receptor (OB-R). Binding of leptin to its receptor results in the activation of the JAK/STAT cell signaling pathway. In mice, mutations in the OB-R or ob genes have resulted in obesity. Although the effects of leptin in humans is less well understood, this protein is present in elevated levels in the plasma of obese individuals. Leptin, by inhibiting fat formation in tissues, improves the function of insulin-producing cells and increases sensitivity of tissues to insulin.

Leukemia Inhibitory Factor (LIF)

LIF is a member of the IL-6 family of cytokines produced by, and influencing, a wide range of cell types. This cytokine has many alternative names. The term LIF can refer to leukaemia inhivitory factor due to its role in inhibiting many myeloid leukemia cells, or as leucocyte migration inhibitory factor due to its role in inhibiting the migration of PMN leucocytes. LIF plays a role in many other activities, including the regulation of early haematopoietic cells, the induction of acute phase protein synthesis and the inhibition of endothelial cell proliferation and adipogensis.

Lymphotactin

Lymphotactin is a member of a newly described chemokine sub-family known as the C sub-family. This chemokine of approximately 10 kDa shares similarities with C-X-C and C-C chemokines, however, it lacks the first and third cysteine residues present in these chemokine sub-families. Lymphotactin is produced by thymocytes and activated T cells and is chemotactic for lymphocytes but not for monocytes or noutrophils.

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M

Monocyte Chemotactic Protein 1 (MCP-1)

Several peptides with monocyte chemotactic activity have been described over the past fiw years. Such monocyte chemotactic proteins (MCPs) belong to the C-C family of chemokines. To date, five human MCPs have been identified (MCP-1, MCP-2, MCP-3, MCP-4 and MCP-5). MCPs 1-5 are chemotactic for monocytes but not for neutrophils. MCP-1 is identical to MCAF (monocyte chemotactic and activating factor) and regulates the expression of cell surface antigens CD11b and CD11c. In addition, this chemokine regulates adhesion molecule expression and cytokine production in monocytes. MCP-1 activates basophils inducing the release of histamines. MCP-1 exhibits other biological activities such as inducing the proliferation and activation of CHAK (C-C chemokine activated killer) cells.

MCP-2, MCP-3, MCP-4 and MCP-5

MCPs 1-5 are related protein that share sequence homology and demonstrate certain overlapping functions. The expression of each MCP appears to be controlled by the actions of varying combinations of cytokines. MCP-2 is produced predominantly by monocytes and osteosarcoma cells and is chemotactic for monocytes and eosinophils. This chemokine is closely related to MCP-1 and MCP-3. MCP-3 was originally identified in osteosarcoma cells and is chemotactic for monocytes, lymphocytes and eosinophils. This factor shares approximately 75% sequence homology with MCP-1. The functions of MCP-4 are very similar to those of MCP-3 and eotaxin. MCP-4 is expressed in epithelial cells following cytokine stimulation. The most recently identified member of the MCP sub-family of chemokines is MCP-5. This protein shares approximately 65% sequence homology with MCP-1. Activated macrophages show an increase in MCP-5 levels.

Macrophage Derived Chemokine (MDC)

MDC is a member of the C-C family of chemokines. The synthesis of MDC to be specifically from cells of the macrophage lineage and is regulated by TH2 cytokines IL-4 and IL-13. MDC appears to be chemotactic for activated TH2 cells. MDC may also be chemotactic for IL-2 activated NK cells and monocyte derived dendritic.

Macrophage Inflammatory Proteins 1a and 1b (MIP-1a and MIP-1b)

MIP-1a and MIP-1b are both acidic proteins belonging to the C-C sub-family of chemokines. Both chemokines are produced by activated macrophages as well as by many other cell types, and have wide ranging effects on a variety of cells. Although MIP-1a and MIP-1b are structurally very similar, there are some sighificant differences in the function of these chemokines. MIP-1a for example, is capable of neutrophil activation, whereas MIP-1b does not activate neutrophils. Fecent research into HIV has identified MIP-1a and MIP-1b as HIV suppressive factors.

MIP-3a and MIP-3b

MIP-3a and MIP-3b belong to the C-C family of chemokines. The receptor for these chemokines has been identified as CCR6. MIP-3b expression seems to be restricted to lymph nodes, appendix and thymus. MIP-3a, however, may also be found expressed in peripheral blood leucocyted and some foetal tissues. Both MIP-3a and MIP-3bare thought to play important chemotactic roles during the inflammatory response.

MIP-4

MIP-4, also known as PARC, is a member of the C-C family of chemokines. This chemokine is chemotactic for T lymphocytes, but does not display any chemotactic activity for macrophages and granulocytes.

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N

Neutrophil Activating Peptide 2 (NAP-2)

NAP-2 is a member of the C-X-C family of chemokines produced predominantly by platelets. This chemokine whilst being related to IL-8, is a less potent chemoattractant of neutrophils. NAP-2 causes neutrophil uptake of calcium, neutrophil degranulation and respiratory burst.

Nerve Growth Factor

Nerve growth factor is a polypeptide growth factor member of the neurotrophin family. Related factors with overlapping, but not identical, activities include the neurotrophins BDNF and NT-3. NGF promotes the differentiation and survival of certain neurons in the sensory and peripheral nervous systems. This growth factor is responsible for the synthesis of various neurotransmitter-like proteins including substance P, vasointestinal peptide and somatostatin. In addition to its neurotrophic activity, NGF is expressed in some non-neuronal tissues. Eosinophils, mast cells, basophils, B cells have also beel shown to express NGF suggesting possible role other than it's neurotrophic functions.

Neurotrophin 3 and Neurotrophin 4 (NT-3 and NT-4)

NT-3 and NT-4 are neurotrophins involved in the control of survival of neuronal cell populations. NT-3 is found in neurons of the central nevous system and is also expressed in muscle tissue. The biological activities of both NT-3 and NT-4 are mediated by receptors of the trk family (trkC receptor for NT-3 and trkB receptor for NT-4) which exhibit tyrosine-specific protein kinase activity. NT-3 and NT-4, as well as sharing approximately 60% sequence homology, share homology with other neurotrophins.

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O

Oncostatin M (OSM)

OSM is a glycoprotein produced by activated monocytes, macrophages and activated T lymphocytes. This protein is a member of the IL-6 family of cytokines and is structurally and functionally related to LIF. OSM inhibits the growth of many cancer cell lines and has a number of effects on cultured endothelial cells, including promoting their growth and regulating endothelial cell expression of colony stimulating factors. OSM acts as a potent growth factor for HIV-related Kaposi sarcoma.

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P

Platelet Derived Growth Factor (PDGF)

PDGF is a growth factor composed of a dimer of two chains known as the A chain and B chain. These chains can be present as AA or BB homodimers or as an AB heterodimer. PDGF is synthesised mainly in megakaryocytes and is released from platelet granules following platelet activation. PDGF is not released into the circulation as is the case for most cytokines, rather it binds to plasma proteins and to extracellular matrix proteins. Two types of PDGF receptor have been cloned, one specific for AA homodimers and another that binds BB and AB type dimers.The receptors have intrinsic tyrosine kinase activity. PDGF AB and PDGF BB are potent mitogens for vascular smooth muscle cells and can induce the expression of a number of proto-oncogenes, such as fos, myx and jun.

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R

RANTES (Regulated on Activation, Normal T cell Expressed and Secreted)

RANTES is a mimber of the C-C family of chemokines. This chemokine is produced in many ccell types including T lymphocytes, monocytesm epithelial cells, NK cells and eosinophils. RANTES is chemotactic for T-cells, basophils and eosinophils. In addition to its chemotactic properties, RANTES demonstrates activation of some cell types such as basophils, NK cells and eosinophils. RANTES acts synergistically with chemokines MIP-1a and MIP-1b in the suppression of certain HIV strains, although the mechanisms by which this is achieved are not yet fully understood.

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S

Stem Cell Factor (SCF)

SCF is an early acting haematopoietic growth factor involved in the stimulation of proliferation of myeloid, erythroid and lymphoid progenitors, SCF appears to act synergistically with colony stimulating factors to exert its biological activities. The receptor for SCF has been identified as the c-kit oncogene (now designated CD117). In vivo studies have shown SCF to promote the promote the proliferation of haematopoietic stem cells and progenitor cells in bone marrow cultures.

Stromal Cell Derived Factor 1 (SDF-1)

SDF-1 is a member of the C-X-C family of chemokines produced constitutively by stromal cells. The production of this chemokine does not appear to be induced by inflammation, as is the case for other chemokines. The receptor for SDF-1 has been identified as CXCR4 (fusin). CXCR4 is known as a co-receptor for T cell trophic HIV strains. When SDF-1 is bound toits receptor, it appears to inhibit T cell trophic HIV infection in vitro. In addition, SDF-1 polymorphisms have been implicated in slowing the progression of disease in HIV infected individuals.

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T

Transforming Growth Factor Alpha (TGF-a)

TGF-a is a growth factor closely related to EGF. The extracellular domain of TGF-a comprises one or more EGF structural units. Both growth factors bind to the same EGF receptor and consequently, display similar biological functions. TGF-a is expressed by many tumours and transformed cells. This growth factor is also expressed in a wide range of normal cells and tissues including pituitary cells, brain, keratinocytes, macrophages, platelets and hepatotytes.

Transforming Growth Factor Beta (TGF-b)

TGF-b is a multifunctional growth factor involved in the regulation of cell growth and differentiation. This growth factor belongs to an increasing family of polypeptide factors sharing structural and functional similarities. TGF-b exists in at least five different isoforns (TGF-b1, TGF-b2, TGF-b3, TGF-b4 and TGF-b5). TGF-b1 is the most prevalent isoform with the others being present in different cells and tissues in varying amounts. Nearly all mammalian cells synthesize and respond to TGF-b, which exerts its effects by binding to TGF-b receptors. A family of glycoprotein receptors for TGF-b has been identified.

Tumour Necrosis Factor Alpha (TNF-a)

TNF-a is cytokine secreted by activated macrephages, monocytes, T cells, neutrophils and NK cells. The actions of TNF-a are numerous and affect a broad range of cell types. Resting macrophages can be induced by TNF-a to synthesize IL-1 and prostaglandin E2. TNF-a, together with other inflammatory cytokines, induces the production ofacute phase proteins from hepatocytes during the inflammatory response. In addition, TNF-a stimulates the expression of MHC class I and class II antigens and the expression of various cytokines and colony stimulating factors. Two receptors for TNF-a, TNF-R1 (55 kDa) and TNF-R2 (75 kDa), have been identified. These have been more recently desighated CD120a and CD120b, respectively. The TNF-R1 contains a so-called death domain, which interacts with proteins such as TRADD and FADD resulting in apoptosis and the activation of the teanscription factor NF-kB. TNF-R2 does not contain a death domain, but is capable of signaling NF-kB activaion.

Tumour Necrosis Factor Beta (TNF-b)

TNF-b, also known as lymphotoxin, is expressed by, and acts on, a wide range of cells. This cytokine demonstrates similar activity to TNF-a although its effects may be less potent. TNF-b induces apoptosis in many types of transformed cells and tumour cells. Fibroblasts can be stimulated by TNF-b to produce certain colony stimulation factors and prostaglandin E2. TNF-b is a B cell mitogen but inhibits osteoclast and keratinocyte growrh.

Thrombopoietin (TPO)

TPO is a cytokine involved in the proliferation and maturation of megakaryocytes. This cytokine promotes an increase in the levels of circulating platelets in vivo and has been identified as the ligand for the cellular mpl oncogene.

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V

Vascular Endothelial Growth Factor (VEGF)

VEGF is a homodimeric glycoprotein growth factor produced by several cell types. At least four VEGF splice variants have been identified, VEGF is a potent mitogen for vascular endothelial cells and seems to possess strong angiogenic activity. The receptor for VEGF is expressed on vascular endothelial cells and is a glycoprotein receptor. Interaction of VEGF with heparin-like molecules is required for efficient binding to the receptor

1.http://bioinformatics.weizmann.ac.il/cgi-bin/cope/cope.pl

2.Vaddi, K., Keller, M., and Newton, R.c.(1997) The Chemokine Factsbook. Acadenic Press.

3.Teran, L.M. and David, D.E,(1996) The chemokines: their potential role in allergic inflammation. Clin. Exp. Allergy 26(9) : 1005-1019

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