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Cytokines   

2008-09-24 16:50:16|  分类: 專業工作 |  标签: |举报 |字号 订阅

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http://www.copewithcytokines.de/cope.cgi?key=Cytokines

The term cytokine, or immunocytokines, was used initially to separate a group of immunomodulatory proteins, called also immunotransmitters, from other Growth factors or regulatory peptide factors that modulate the proliferation and bioactivities of non-immune cells. However, this terminology suggesting a clear-cut distinction cannot be maintained and may not be meaningful altogether. Some cytokines are produced by a rather limited number of different cell types while others are produced by almost the entire spectrum of known cell types.

The initial concept of "one producer cell - one cytokine - one target cell" has been falsified for practically every cytokine investigated more closely. A definition of these factors on the basis of their producer or target cells is therefore also problematic.

The same applies to classifications based upon identical or shared biological activities of cytokines especially with broad definitions (see, for example: BCDF (B-cell differentiation factors), BCGF (B-cell growth factors), Motogenic cytokines, Chemotactic cytokines (see: Chemokines), CSF (colony stimulating factors), angiogenesis factors, or TRF (T-cell replacing factors)) (for some personal views on aspects of nomenclature see also: Some personal remarks).

Designations such as HBGF (heparin binding growth factors) take into account some biochemical shared by a variety of cytokines but are also problematic.

Today the term cytokine is used as a generic name for a diverse group of soluble proteins and peptides that act as humoral regulators at nano- to picomolar concentrations and which, either under normal or pathological conditions, modulate the functional activities of individual cells and tissues. These proteins also mediate interactions between cells directly and regulate processes taking place in the extracellular environment (for some mechanistic concepts underlying cytokine actions see also: autocrine, paracrine, juxtacrine, retrocrine). Many growth factors and cytokines act as cellular survival factors by preventing programmed cell death (see: Apoptosis).

In many respects the biological activities of cytokines resemble those of classical hormones produced in specialized glandular tissues. Some cytokines also behave like classical hormones in that they act at a systemic level, affecting, for example, biological phenomena such as inflammation, systemic inflammatory response syndrome, and acute phase reaction, wound healing, and the neuroimmune network.

In general, cytokines act on a wider spectrum of target cells than hormones. Perhaps the major feature distinguishing cytokines from mediators regarded generally as hormones is the fact that, unlike hormones, cytokines are not produced by specialized cells organized in specialized glands, i.e., there is not a single organ source for these mediators. The fact that cytokines are secreted proteins also means that the sites of their expression does not necessarily predict the sites at which they exert their biological function.

Some cytokines have been found, upon determination of their primary structures, to be identical with classical enzymes or other types of proteins with well known and cytokine-unrelated functions in biochemistry, cell biology, and physiology (see: Dual identity proteins MiniCOPE Dictionary). Cytokines normally do not possess enzymatic activities although there is a growing list of exceptions.

The biological activities of cytokines can be measured by a variety of bioassays employing, among other things, Factor-dependent cell lines, or by other assays using, for example, antibodies (see also: cytokine assays, WHO cytokine standardization). RT-PCR quantitation of cytokines employs modern techniques of molecular biology and detects the presence of mRNA encoding specific cytokines.

In the more restricted sense cytokines comprise Interleukins, initially thought to be produced exclusively by leukocytes, Lymphokines, initially thought to be produced exclusively by lymphocytes, Monokines, initially thought to be produced exclusively by monocytes, interferons (see: IFN), initially thought to be involved in antiviral responses, colony stimulating factors (see: CSF), initially thought to support the growth of cells in semi-solid media (see also: Colony formation assay), Chemokines, thought to be involved in Chemotaxis, and a variety of other proteins.

The term Type 1 cytokines refers to cytokines produced by Th1 T-helper cells while Type 2 cytokines are those produced by Th2 T-helper cells. Type 1 cytokines include IL2, IFN-gamma, IL12 and TNF-beta, while Type 2 cytokines include IL4, IL5, IL6, IL10, and IL13.

It has been suggested that the generic term Peptide regulatory factors (abbr. PRF) be used for all these factors to avoid the general difficulties with the nomenclature (see also: Some personal remarks). This term has the advantage that it includes also a number of low molecular mass peptides, which are generally not regarded as cytokines although they have many activities of cytokines. Some of these low molecular weight proteins and peptides have been referred to as regulatory peptide factors.

A comparison of sequences demonstrates that nonhuman primate cytokines are closely related. For example, IL1-alpha, IL1-beta, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL15, IFN-alpha, IFN-gamma, and TNF-alpha share 93 to 99 % homology at the nucleic acid and protein level with the human orthologous sequences (Villinger et al, 1995). Cytokines from other species are frequently detected by virtue of sequence homologies (for activities of cytokines from one species in another species see also: Cytokine Inter-species Reactivities).

Most cytokines are unrelated in terms of sequence although some can be grouped into families (see: gene family; see also: Cytokine receptor families) or are classified into categories according to the types of secondary and tertiary structure. For example, IL6, IL11, CNTF, LIF, OSM, Epo, G-CSF, GH, PRL, IL10, IFN-alpha, IFN-beta form  long chain 4 helix bundles. IL2, IL4, IL7, IL9, IL13, IL3, IL5, GM-CSF, M-CSF, SCF, IFN-gamma form  short chain 4 helix bundles. So-called beta-trefoil structures are formed by IL1-alpha, IL1-beta, aFGF, bFGF, int-2, KGF. EGF-like antiparallel beta-sheets are formed by EGF, TGF-alpha, Betacellulin, SCDGF, Amphiregulin, HB-EGF. For other aspects of biochemistry see also: Recombinant cytokines, Muteins, Peptide mimetics.

Most cytokines are glycoproteins that are secreted by cells using classical secretory pathways (see also: signal sequence). Many genes encoding cytokines can give rise to a variety of variant forms of cytokines by means of alternative splicing, yielding molecules with slightly different but biologically significant bioactivities. In many cases the expression patterns of different forms of cytokines or of members of a cytokine family are overlapping only partially, suggesting a specific role for each factor.

Membrane-bound forms have been described also for many cytokines, and some may be associated also with the extracellular matrix. It is likely that the switching between soluble and membrane forms of cytokines is an important regulatory event (see also: Autocrine, paracrine, juxtacrine, retrocrine). In some cases membrane forms of a cytokine have been found to be indispensable for normal development, with soluble forms being unable to entirely substitute for them.

Most cytokines are generally not stored inside cells (exceptions are, for example TGF-beta and PDGF stored in platelets or preformed TNF-alpha and IL8 found in human skin mast cells. The expression of most cytokines is regulated tightly at practically all levels: these factors are usually produced only by cells after cell activation in response to an induction signal. The production and secretion of cytokines and growth factors frequently is context dependent, i.e., their expression is influenced by individual signals received but also by the balance of signals received through one or more receptors (which themselves may be subject to inducible/repressible expression).

Expression can be regulated at the level of transcription, translation, and protein synthesis (see also: gene expression; AU-rich element). Normally, cytokines are expressed transiently only but constitutive expression has been observed also. The expression of many cytokines also seems to be regulated differentially, depending on cell type and developmental age. Secretion or release from producer cells is a regulated process. Once released, their behaviour in the circulation may be regulated by soluble receptors and specific or unspecific binding proteins. Regulation also is at work at the receptor level on target cells and at the level of signaling pathways governing alterations in the behaviour of responder cells.

Most cytokines were detected initially in functional tests in vitro as biochemically undefined activities or as distinct factors with distinct biological activities. This also explains, at least in part, the plethora of different names for some of the cytokines. In many instances these activities were named after a particular biological activity observed in an in vitro assay (see also: bioassays and cytokine assays for alternatives) or after cells that were found to elaborate these factors (for techniques allowing identification of cytokine genes, cytokine receptor genes, and other relevant genes without prior knowledge of their activities see: gene library). One should be aware of the fact that at this moment in time the relevance of many in vitro activities of cytokines to their endogenous functions within an intact organism is not clearly defined.

Almost all cytokines are pleiotropic effectors showing multiple biological activities. In addition, multiple cytokines often have overlapping activities and a single cell frequently interacts with multiple cytokines with seemingly identical responses (cross-talk). One of the consequences of this functional overlap is the observation that one factor may frequently functionally replace another factor altogether or at least partially compensate for the lack of another factor. Since most cytokines have ubiquitous biological activities, their physiologic significance as normal regulators of physiology is often difficult to assess.

Studies of gene functions in experimental transgenic knock-out animals in which a cytokine gene has been functionally inactivated by gene targeting are of particular importance in research on cytokines because, unlike in vitro studies, they provide information about the true in vivo functions of a given cytokine by highlighting the effects of their absence. In many instances these studies have shown that null mutations of particular cytokine genes do not have the effects in vivo expected from their activities in vitro. If information about loss-of-function studies is available for a given cytokine or its receptor and if I had time to add the information it can be found as a special subentry (Transgenic /Knock-out/Antisense studies) for each particular cytokine.

Many cytokines show stimulating or inhibitory activities and may synergise or antagonize also the actions of other factors. A single cytokine may elicit reactions also under certain circumstances that are the reverse of those shown under other circumstances. The type, the duration, and also the extent of cellular activities induced by a particular cytokine can be influenced considerably by the micro-environment of a cell, depending, for example, on the growth state of the cells (sparse or confluent), the type of neighboring cells, cytokine concentrations, the combination of other cytokines present at the same time, and even on the temporal sequence of several cytokines acting on the same cell. Under such circumstances combinatorial effects thus allow a single cytokine to transmit diverse signals to different subsets of cells.

The fact that every cell type may have different responses to the same growth factor can be explained, at least in part, by different spectrums of genes expressed in these cells and the availability and levels of various transcription factors that drive Gene expression. The responses elicited by cytokines are therefore contextual and the "informational content", i.e., the intrinsic activities of a given cytokine may vary with conditions. Although a variety of cytokines are known to share at least some biological effects the observations that single cells usually show different patterns of gene expression in response to different cytokines can be taken as evidence for the existence of cytokine receptor-specific signal transduction pathways. Shared and different transcriptional activators that transduce a signal from a cytokine receptor to a transcription regulatory element of DNA are involved in these processes (for some examples see: STAT proteins, Janus kinases, IRS).

It has been observed, for example, that bFGF is a strong mitogen for fibroblasts at low concentrations and a chemoattractant at high concentrations (see also: Chemotaxis). bFGF has been shown also to be a biphasic regulator of human hepatoblastoma-derived HepG2 cells, depending upon concentration. The interferon IFN-gamma can stimulate the proliferation of B-cells prestimulated with Anti-IgM, and inhibits the activities of the same cells induced by IL4. On the other hand, IL4 activates B-cells and promotes their proliferation while inhibiting the effects induced by IL2 in the same cells. The activity of at least two cytokines (IL1-alpha and IL1-beta) is regulated by an endogenous receptor antagonist, the IL1 receptor antagonist (see: IL1ra). Several cytokines, including TNF, IFN-gamma, IL2 and IL4, are inhibited by soluble receptors (see also: Receptor shedding, Cytokine inhibitors, retrocrine). Several cytokines, including IL10 and TGF-beta, act to inhibit other cytokines.

The processes responsible for the regulation of cytokines are not well understood. Cells utilize distinct biochemical pathways converging on mediator release and these can be probed, among other things, by employing a variety of substances mimicking or inhibiting the actions of cytokines (see, for example: Bryostatins, Calcium ionophore, Genistein, H8, Herbimycin A, K-252a, Lavendustin A, Phorbol esters, Okadaic acid, Staurosporine, Suramin, Tyrphostins, Vanadate).

Frequently one observes a hierarchical order of cytokine actions with some early Cytokines preactivating cells so that they then can respond to late-acting cytokines (see also: cell activation). Many cytokines induce the synthesis of novel gene products once they have bound to their respective receptors (see also: Early response gene). Some of the novel products are themselves cytokines (see: Chemokines, for example). In addition, there are a variety of biological response modifiers that function as Anti-cytokines.

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 possibilities by far exceed the possibilities provided by mere cell-to-cell contacts within a multicellular organism. It can be assumed that cytokines play a pivotal role in all sorts of cell-to-cell communication processes although many of the mechanisms of their actions have not yet been elucidated in full detail.

A close examination of the physiological and pathological effects of the regulated or deregulated (see: transgenic animals) expression of cytokines in complex organisms has shown that these mediators are involved in virtually all general systemic reactions of an organism (see also: CytokineTopics), including such important processes as the regulation of immune responses (see, for example: BCDF, B-cell growth and differentiation factors; BCGF, B-cell growth factors; TRF, T-cell replacing factors; Isotype switching), inflammatory processes (see: inflammation), hematopoiesis (see also: Hematopoietins), and wound healing.

Cytokines are important mediators involved in embryogenesis and organ development (see also: Angiogenesis) and their activities in these processes may differ from those observed postnatally. In addition they play a key role in neuroimmunological, neuroendocrinological, and neuroregulatory processes (see: Neuroimmune network). Cytokines are important positive or negative regulators of the cell cycle, differentiation, migration (see also: Chemotaxis, Chemokines), cell survival and cell death, and cell transformation. It has been shown that a number of viral infectious agents exploit the cytokine repertoire of organisms to evade immune responses of the host. Virus-encoded factors (see also: Virulence Factors MiniCOPE Dictionary.) 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; by inhibiting signal transmission pathways of cytokines; and by synthesizing virus-encoded cytokines that antagonize the effects of host cytokines mediating antiviral processes (see: Viroceptor, Virokine). Bacteria and other micro-organisms also appear to produce substances with activities resembling those of cytokines and which they utilize to subvert host responses (see: Bacteriokine, Microkine).

Cytokines themselves rarely are related closely among each other in terms of primary sequences. Some appear to have some common three-dimensional features and some of them can be grouped into families. For example, the TNF ligand superfamily members (with the exception of LT-alpha) are type 2 membrane glycoproteins (N-terminus inside) with homology to TNF in the extracellular domain (overall homologies, 20 %. The HBNF family includes members of the group of fibroblast growth factors. Another group of diverse factors with conserved sequence features are the Chemokines. The analysis of crystal structures of several cytokines with very little sequence homology has revealed a common overall topology that is not deducible from sequence comparisons (see: Cystine knot growth factor family).

The biological activities of cytokines are mediated by specific membrane receptors, which can be expressed on virtually all cell types known. Their expression is also subject to several regulatory mechanisms (see: Receptor transmodulation) although some receptors are expressed also constitutively.

Cytokine receptor proteins have been shown to share a number of characteristics. Many receptors are members of cytokine receptor families. Many receptors are multi-subunit structures that bind ligands and at the same time possess functions as signal transducers due to their intrinsic tyrosine kinase activity (see also: Autophosphorylation). Many receptors often share common signal transducing receptor components in the same family (see also: Cytokine receptor families), which explains, at least in part, the functional redundancy of cytokines. It is the cross-communication between different signaling systems that eventually allows the integration of a great diversity of stimuli, which a cell can be subjected to under varying physiological situations. This and the ubiquitous cellular distribution of certain cytokine receptors has hampered attempts to define critical responsive cell populations and the physiologically important cell-specific functions of cytokines in vivo. Many receptors are associated with special signal transducing proteins in the interior of the cell (see, for example Janus kinases, STAT proteins). Some receptors may bind more than one cytokine. Several cytokine receptors have been shown to be converted into soluble binding proteins that regulate ligand access to the cell by specific proteolytic cleavage of receptor ectodomains.

The many specific activities of individual cytokines have been the basis for current concepts of therapeutical intervention, in particular of the treatment of hematopoietic malfunctions and tumor therapy. Applications involve the support of chemo- and radiotherapy, bone marrow transplantation, and general immunostimulation (see also: Adoptive immunotherapy, LAK cells, TIL, Cytokine gene transfer, Cytokine fusion toxins).

Although some recombinant cytokines are now in clinical use, and attempts are made to develop hybrid molecules from known cytokines (see: Muteins) which possess the advantages of the respective factors, but not their disadvantages, one must be aware of the fact that current knowledge is still limited. Cytokines are powerful two-edged weapons that can trigger a cascade of reactions, and may show activities that often go beyond the single highly specific property that it is hoped they possess. New factors are being discovered constantly and they extend our knowledge about the Cytokine network.

Nevertheless it can be stated that our new (and growing) understanding of the biological mechanisms governing cytokine actions are an important contribution to medical knowledge. The biochemistry and molecular biology of cytokine actions explain some well-known and sometimes also some of the more obscure clinical aspects of diseases. Knowledge that cytokines create regulatory hierarchies and provide independent and/or interrelated regulatory mechanisms that can confer distinct and interactive developmental functions lays a solid, albeit rather complicated foundation, for current and future clinical experiences.


http://en.wikipedia.org/wiki/Cytokines

Cytokines are a category of signalling proteins and glycoproteins that, like hormones and neurotransmitters, are used extensively in cellular communication. While hormones are secreted from specific organs to the blood, and neurotransmitters are related to neural activity, the cytokines are a more diverse class of compounds in terms of origin and purpose. They are produced by a wide variety of hematopoietic and non-hematopoietic cell types and can have autocrine, paracrine and endocrine effects, sometimes strongly dependent on the presence of other chemicals. The cytokine family consists mainly of smaller, water-soluble proteins and glycoproteins with a mass between 8 and 30 kDa.

Cytokines are critical to the development and functioning of both the innate and adaptive immune response. They are often secreted by immune cells that have encountered a pathogen, thereby activating and recruiting further immune cells to increase the system's response to the pathogen. Cytokines are also involved in several developmental processes during embryogenesis.

Growth factors are proteins that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type. The lists in the following Tables as well as the descriptions of several factors are not intended to be comprehensive nor complete but a look at some of the more commonly known factors and their principal activities.

Factor Principal Source Primary Activity Comments
PDGF platelets, endothelial cells, placenta promotes proliferation of connective tissue, glial and smooth muscle cells two different protein chains form 3 distinct dimer forms; AA, AB and BB
EGF submaxillary gland, Brunners gland promotes proliferation of mesenchymal, glial and epithelial cells  
TGF-a common in transformed cells may be important for normal wound healing related to EGF
FGF wide range of cells; protein is associated with the ECM promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos at least 19 family members, 4 distinct receptors
NGF   promotes neurite outgrowth and neural cell survival several related proteins first identified as proto-oncogenes; trkA (trackA), trkB, trkC
Erythropoietin kidney promotes proliferation and differentiation of erythrocytes  
TGF-b activated TH1 cells (T-helper) and natural killer (NK) cells anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation at least 100 different family members
IGF-I primarily liver promotes proliferation of many cell types related to IGF-II and proinsulin, also called Somatomedin C
IGF-II variety of cells promotes proliferation of many cell types primarily of fetal origin related to IGF-I and proinsulin

Cytokines are a unique family of growth factors. Secreted primarily from leukocytes, cytokines stimulate both the humoral and cellular immune responses, as well as the activation of phagocytic cells. Cytokines that are secreted from lymphocytes are termed lymphokines, whereas those secreted by monocytes or macrophages are termed monokines. A large family of cytokines are produced by various cells of the body. Many of the lymphokines are also known as interleukins (ILs), since they are not only secreted by leukocytes but also able to affect the cellular responses of leukocytes. Specifically, interleukins are growth factors targeted to cells of hematopoietic origin. The list of identified interleukins grows continuously with the total number of individual activities now at 22 (13 are listed in the Table below).

Interleukins Principal Source Primary Activity
IL1-a and -b macrophages and other antigen presenting cells (APCs) costimulation of APCs and T cells, inflammation and fever, acute phase response, hematopoiesis
IL-2 activated TH1 cells, NK cells proliferation of B cells and activated T cells, NK functions
IL-3 activated T cells growth of hematopoietic progenitor cells
IL-4 TH2 and mast cells B cell proliferation, eosinophil and mast cell growth and function, IgE and class II MHC expression on B cells, inhibition of monokine production
IL-5 TH2 and mast cells eosinophil growth and function
IL-6 activated TH2 cells, APCs, other somatic cells acute phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1 and TNF on T cells
IL-7 thymic and marrow stromal cells T and B lymphopoiesis
IL-8 macrophages, other somatic cells chemoattractant for neutrophils and T cells
IL-9 T cells hematopoietic and thymopoietic effects
IL-10 activated TH2 cells, CD8+ T and B cells, macrophages inhibits cytokine production, promotes B cell proliferation and antibody production, suppresses cellular immunity, mast cell growth
IL-11 stromal cells synergisitc hematopoietic and thrombopoietic effects
IL-12 B cells, macrophages proliferation of NK cells, INF-g production, promotes cell-mediated immune functions
IL-13 TH2 cells IL-4-like activities
Interferons Principal Source Primary Activity
INF-a and -b macrophages, neutrophils and some somatic cells antiviral effects, induction of class I MHC on all somatic cells, activation of NK cells and macrophages
INF-g activated TH1 and NK cells induces of class I MHC on all somatic cells, induces class II MHC on APCs and somatic cells, activates macrophages, neutrophils, NK cells, promotes cell-mediated immunity, antiviral effects

EGF, like all growth factors, binds to specific high-affinity, low-capacity receptors on the surface of responsive cells. Intrinsic to the EGF receptor is tyrosine kinase activity, which is activated in response to EGF binding. The kinase domain of the EGF receptor phosphorylates the EGF receptor itself (autophosphorylation) as well as other proteins, in signal transduction cascades, that associate with the receptor following activation. Experimental evidence has shown that the Neu proto-oncogene is a homologue of the EGF receptor.

EGF has proliferative effects on cells of both mesodermal and ectodermal origin, particularly keratinocytes and fibroblasts. EGF exhibits negative growth effects on certain carcinomas as well as hair follicle cells. Growth-related responses to EGF include the induction of nuclear proto-oncogene expression, such as Fos, Jun and Myc. EGF also has the effect of decreasing gastric acid secretion. .

PDGF is composed of two distinct polypeptide chains, A and B, that form homodimers (AA or BB) or heterodimers (AB). The c-Sis proto-oncogene has been shown to be homologous to the PDGF A chain. Only the dimeric forms of PDGF interact with the PDGF receptor. Two distinct classes of PDGF receptor have been cloned, one specific for AA homodimers and another that binds BB and AB type dimers. Like the EGF receptor, the PDGF receptors have intrinsic tyrosine kinase activity. Following autophosphorylation of the PDGF receptor, numerous signal-transducing proteins associate with the receptor and are subsequently tyrosine phosphorylated.

Proliferative responses to PDGF action are exerted on many mesenchymal cell types. Other growth-related responses to PDGF include cytoskeletal rearrangement and increased polyphosphoinositol turnover. Again, like EGF, PDGF induces the expression of a number of nuclear localized proto-oncogenes, such as Fos, Myc and Jun. The primary effects of TGF-b are due to the induction, by TGF-b, of PDGF expression.

There are at least 19 distinct members of the FGF family of growth factors. The two originally characterized FGFs were identified by biological assay and are termed FGF1 (acidic-FGF, aFGF) and FGF2 (basic-FGF, bFGF). Kaposi's sarcoma cells (prevalent in patients with AIDS) secrete a homologue of FGF called the K-FGF proto-oncogene. In mice the mammary tumor virus integrates at two predominant sites in the mouse genome identified as Int-1 and Int-2. The protein encoded by the Int-2 locus is a homologue of the FGF family of growth factors.

Studies of human disorders as well as gene knock-out studies in mice show the prominent role for FGFs is in the development of the skeletal system and nervous system in mammals. FGFs also are neurotrophic for cells of both the peripheral and central nervous system. Additionally, several members of the FGF family are potent inducers of mesodermal differentiation in early embryos. Non-proliferative effects include regulation of pituitary and ovarian cell function.
 
The FGFs interact with specific cell-surface receptors. There have been identified 4 distinct receptor types identified as FGFR1 - FGFR4. Each of these receptors has intrinsic tyrosine kinase activity like both the EGF and PDGF receptors. As with all transmembrane receptors that have tyrosine kinase activity, autophosphorylation of the receptor is the immediate response to FGF binding. Following activation of FGF receptors, numerous signal-transducing proteins associate with the receptor and become tyrosine-phosphorylated. The Flg proto-oncogene is a homologue of the FGF receptor family. The FGFR1 receptor also has been shown to be the portal of entry into cells for herpes viruses. FGFs also bind to cell-surface heparan-sulfated proteoglycans with low affinity relative to that of the specific receptors. The purpose in binding of FGFs to theses proteoglycans is not completely understood but may allow the growth factor to remain associated with the extracellular surface of cells that they are intended to stimulate under various conditions.
 
The FGF receptors are widley expressed in developing bone and several common autosomal dominant disorders of bone growth have been shown to result from mutations in the FGFR genes. The most prevalent is achondroplasia, ACH. ACH is characterized by disproportionate short stature, where the limbs are shorter than the trunk, and macrocephaly (excessive head size). Almost all persons with ACH exhibit a glycine to arginine substitution in the transmembrane domain of FGFR3. This mutation results in ligand-independent activation of the receptor. FGFR3 is predominantly expressed in quiescent chondrocytes where it is responsible for restricting chondrocyte proliferation and differentiation. In mice with inactivating mutations in FGFR3 there is an expansion of long bone growth and zones of proliferating cartilage further demonstrating that FGFR3 is necessary to control the rate and amount of chondrocyte growth.
Several other disorders of bone growth collectively identified as craniosynostosis syndromes have been shown to result from mutations in FGFR1, FGFR2 and FGFR3. Sometimes the same mutation can cause two or more different craniosynostosis syndromes. A cysteine to tyrosine substitution in FGFR2 can cause either Pfeiffer or Crouzon syndrome. This phenomenon indicates that additional factors are likely responsible for the different phenotypes.
Affected Receptor Syndrome Phenotypes
FGFR1 Pfeiffer broad first digits, hypertelorism
FGFR2 Apert mid-face hypoplasia, fusion of digits
FGFR2 Beare-Stevenson mid-face hypoplasia, corrugated skin
FGFR2 Crouzon mid-face hypoplasia, ocular proptosis
FGFR2 Jackson-Weiss mid-face hypoplasia, foot anamolies
FGFR2 Pfeiffer same as for FGFR1 mutations
FGFR3 Crouzon mid-face hypoplasia, acanthosis nigricans, ocular proptosis
FGFR3 Non-syndromatic craniosynostosis digit defects, hearing loss

A more detailed description of the TGF-b family of growth factors and associated signaling pathways can be found on the Signaling by Wnts and TGFs-b/BMP page.

TGF-b was originally characterized as a protein (secreted from a tumor cell line) that was capable of inducing a transformed phenotype in non-neoplastic cells in culture. This effect was reversible, as demonstrated by the reversion of the cells to a normal phenotype following removal of the TGF-b. Subsequently, many proteins homologous to TGF-b have been identified. The four closest relatives are TGF-b-1 (the original TGF-b) through TGF-b-5 (TGF-b-1 = TGF-b-4). All four of these proteins share extensive regions of similarity in their amino acids. Many other proteins, possessing distinct biological functions, have stretches of amino-acid homology to the TGF-b family of proteins, particularly the C-terminal region of these proteins.

The TGF-b-related family of proteins includes the activin and inhibin proteins. There are activin A, B and AB proteins, as well as an inhibin A and inhibin B protein. The Mullerian inhibiting substance (MIS) is also a TGF-b-related protein, as are members of the bone morphogenetic protein (BMP) family of bone growth-regulatory factors. Indeed, the TGF-b family may comprise as many as 100 distinct proteins, all with at least one region of amino-acid sequence homology.

There are several classes of cell-surface receptors that bind different TGF-b with differing affinities. There also are cell-type specific differences in receptor sub-types. Unlike the EGF, PDGF and FGF receptors, the TGF-b family of receptors all have intrinsic serine/threonine kinase activity and, therefore, induce distinct cascades of signal transduction.
 

TGFs-b have proliferative effects on many mesenchymal and epithelial cell types. Under certain conditions TGFs-b will demonstrate anti-proliferative effects on endothelial cells, macrophages, and T- and B-lymphocytes. Such effects include decreasing the secretion of immunoglobulin and suppressing hematopoiesis, myogenesis, adipogenesis and adrenal steroidogenesis. Several members of the TGF-b family are potent inducers of mesodermal differentiation in early embryos, in particular TGF-b and activin A.

Transforming Growth Facor-a (TGF-a)

TGF-a, like the b form, was first identified as a substance secreted from certain tumor cells that, in conjunction with TGF-b-1, could reversibly transform certain types of normal cells in culture. TGF-a binds to the EGF receptor, as well as its own distinct receptor, and it is this interaction that is thought to be responsible for the growth factor's effect. The predominant sources of TGF-a are carcinomas, but activated macrophages and keratinocytes (and possibly other epithelial cells) also secrete TGF-a. In normal cell populations, TGF-a is a potent keratinocyte growth factor; forming an autocrine growth loop by virtue of the protein activating the very cells that produce it.

Epo is synthesized by the kidney and is the primary regulator of erythropoiesis. Epo stimulates the proliferation and differentiation of immature erythrocytes; it also stimulates the growth of erythoid progenitor cells (e.g. erythrocyte burst-forming and colony-forming units) and induces the differentiation of erythrocyte colony-forming units into proerythroblasts. When patients suffering from anemia due to kidney failure are given Epo, the result is a rapid and significant increase in red blood cell count.


IGF-I (originally called somatomedin C) is a growth factor structurally related to insulin. IGF-I is the primary protein involved in responses of cells to growth hormone (GH): that is, IGF-I is produced in response to GH and then induces subsequent cellular activities, particularly on bone growth. It is the activity of IGF-I in response to GH that gave rise to the term somatomedin. Subsequent studies have demonstrated, however, that IGF-I has autocrine and paracrine activities in addition to the initially observed endocrine activities on bone. The IGF-I receptor, like the insulin receptor, has intrinsic tyrosine kinase activity. Owing to their structural similarities IGF-I can bind to the insulin receptor but does so at a much lower affinity than does insulin itself.

IGF-II is almost exclusively expressed in embryonic and neonatal tissues. Following birth, the level of detectable IGF-II protein falls significantly. For this reason IGF-II is thought to be a fetal growth factor. The IGF-II receptor is identical to the mannose-6-phosphate receptor that is responsible for the integration of lysosomal enzymes (which contain mannose-6-phosphate residues) to the lysosomes.

IL-1 is one of the most important immune response -- modifying interleukins. The predominant function of IL-1 is to enhance the activation of T-cells in response to antigen. The activation of T-cells, by IL-1, leads to increased T-cell production of IL-2 and of the IL-2 receptor, which in turn augments the activation of the T-cells in an autocrine loop. IL-1 also induces expression of interferon-g (IFN-g) by T-cells. This effect of T-cell activation by IL-1 is mimicked by TNF-a which is another cytokine secreted by activated macrophages. There are 2 distinct IL-1 proteins, termed IL-1-a and -1-b, that are 26% homologous at the amino acid level. The IL-1s are secreted primarily by macrophages but also from neutrophils, endothelial cells, smooth muscle cells, glial cells, astrocytes, B- and T-cells, fibroblasts and keratinocytes. Production of IL-1 by these different cell types occurs only in response to cellular stimulation. In addition to its effects on T-cells, IL-1 can induce proliferation in non-lymphoid cells.

IL-2, produced and secreted by activated T-cells, is the major interleukin responsible for clonal T-cell proliferation. IL-2 also exerts effects on B-cells, macrophages, and natural killer (NK) cells. The production of IL-2 occurs primarily by CD4+ T-helper cells. As indicated above, the expression of both IL-2 and the IL-2 receptor by T-cells is induced by IL-1. Indeed, the IL-2 receptor is not expressed on the surface of resting T-cells and is present only transiently on the surface of T-cells, disappearing within 6-10 days of antigen presentation. In contrast to T-helper cells, NK cells constitutively express IL-2 receptors and will secrete TNF-a, IFN-g and GM-CSF in response to IL-2, which in turn activate macrophages.

IL-6 is produced by macrophages, fibroblasts, endothelial cells and activated T-helper cells. IL-6 acts in synergy with IL-1 and TNF-( in many immune responses, including T-cell activation. In particular, IL-6 is the primary inducer of the acute-phase response in liver. IL-6 also enhances the differentiation of B-cells and their consequent production of immunoglobulin. Glucocorticoid synthesis is also enhanced by IL-6. Unlike IL-1, IL-2 and TNF-a, IL-6 does not induce cytokine expression; its main effects, therefore, are to augment the responses of immune cells to other cytokines.

IL-8 is an interleukin that belongs to an ever-expanding family of proteins that exert chemoattractant activity to leukocytes and fibroblasts. This family of proteins is termed the chemokines. IL-8 is produced by monocytes, neutrophils, and NK cells and is chemoattractant for neutrophils, basophils and T-cells. In addition, IL-8 activates neutrophils to degranulate.

TNF-a (also called cachectin), like IL-1 is a major immune response-- modifying cytokine produced primarily by activated macrophages. Like IL-1, TNF-a induces the expression of other autocrine growth factors, increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation. TNF-a acts synergistically with EGF and PDGF on some cell types. Like other growth factors, TNF-a induces expression of a number of nuclear proto-oncogenes as well as of several interleukins.

TNF-b (also called lymphotoxin) is characterized by its ability to kill a number of different cell types, as well as the ability to induce terminal differentiation in others. One significant non-proliferative response to TNF-b is an inhibition of lipoprotein lipase present on the surface of vascular endothelial cells. The predominant site of TNF-b synthesis is T-lymphocytes, in particular the special class of T-cells called cytotoxic T-lymphocytes (CTL cells). The induction of TNF-b expression results from elevations in IL-2 as well as the interaction of antigen with T-cell receptors.

IFN-a, IFN-b and IFN-w are known as type I interferons: they are predominantly responsible for the antiviral activities of the interferons. In contrast, IFN-g is a type II or immune interferon. Although IFN-g, has antiviral activity it is significantly less active at this function than the type I IFNs. Unlike the type I IFNs, IFN-g is not induced by infection nor by double-stranded RNAs. IFN-g is secreted primarily by CD8+ T-cells. Nearly all cells express receptors for IFN-g and respond to IFN-g binding by increasing the surface expression of class I MHC proteins, thereby promoting the presentation of antigen to T-helper (CD4+) cells. IFN-g also increases the presentation of class II MHC proteins on class II cells further enhancing the ability of cells to present antigen to T-cells.

CSFs are cytokines that stimulate the proliferation of specific pluripotent stem cells of the bone marrow in adults. Granulocyte-CSF (G-CSF) is specific for proliferative effects on cells of the granulocyte lineage. Macrophage-CSF (M-CSF) is specific for cells of the macrophage lineage. Granulocyte-macrophage-CSF (GM-CSF) has proliferative effects on both classes of lymphoid cells. Epo is also considered a CSF as well as a growth factor, since it stimulates the proliferation of erythrocyte colony-forming units. IL-3 (secreted primarily from T-cells) is also known as multi-CSF, since it stimulates stem cells to produce all forms of hematopoietic cells.

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