Progress in growth factor research最新文献

Since the original description of interleukin-10, a wealth of information concerning its biological properties has been gathered. Studies in vitro have rapidly identified both immunostimulatory and immunosuppressive activities for IL-10. Based on these findings, in vivo studies were initiated in a variety of animal disease models to assess the importance of these activities. This review will summarize the pleiotropic properties of IL-10 and will survey current research regarding the potential of IL-10 to regulate acute and chronic inflammatory reactions.

Transforming growth factor-β is a pluripotent regulator of cell growth and differentiation. The growth factor is expressed as a latent complex that must be converted to an active form before interacting with its ubiquitous high affinity receptors. This conversion involves the release of the mature growth factor through disruption of the non-covalent interactions with its pro-peptide or latency associated peptide. The mechanisms for this release in vivo have not been fully characterized but appear to be cell specific and might involve processes such as acidification or proteolysis. Although several factors including transcriptional regulation, receptor modulation and scavenging of the active growth factor have been implicated, the critical step controlling the biological effects of transforming growth factor-β may be the activation of the latent molecule.

This review considers the biology of the type 1 growth factor receptor family which is increasingly recognised as important in the control of normal cell proliferation and in the pathogenesis of human cancer. The family currently comprises three closely related members: the epidermal growth factor (EGF) receptor, c-erbB-2 and c-erbB-3, all of which show abnormalities of expression in various human tumours. The family of factors related to EGF has also expanded recently and now includes transforming growth factor alpha, heparin-binding EGF, amphiregulin, cripto and heregulin, as well as several other potential ligands for the c-erbB2-2 receptor. The involvement of these receptors and growth factors in human cancer has implications for the design of novel forms of therapy for cancer, and we review recent advances and future avenues for investigation.

The insulin receptor and type I IGF receptor are closely related in structure and function. The receptors are heterotetrameric glycoproteins, of structure αββα, which are widely distributed in mammalian tissues. A third member of this receptor family has been described, the insulin receptor-related receptor, for which a ligand has still to be identified. It has also been demonstrated that the insulin receptor and IGF receptor form αββ′α′ hybrids in cells expressing both receptors.

The key elements in the function of any receptor are recognition of ligand and transmission of an intracellular signal. In the insulin and IGF receptors, determinants of binding specificity are contained within amino-terminal and cysteine-rich domains of the extracellular α-subunit. Intracellular signalling is dependent on ligand activated tyrosine kinase activity in the transmembrane β-subunit, which phosphorylates both the receptor itself and the specific substrate insulin receptor substrate-1 (IRS-1). Phosphorylated IRS-1 binds the enzyme phosphatidylinositol 3-kinase and may act as a multivalent docking site for SH2 domains of other proteins involved in signalling. The possibility that some signalling molecules interact directly with the receptors has not been ruled out.

The specificity of action of insulin and IGFs in vivo depends on differences between the respective receptors in tissue distribution, ligand binding specificity and intrinsic signalling capacity. However, the detailed aspects of gene and receptor structure which underly these functional differences are still poorly understood. Moreover, the issue of specificity is complicated by the existence of hybrid and atypical receptors, which in principle could bind and respond to both insulin and IGF-I, although the physiological significance of these receptor subtypes is at present unclear.

Natural Killer cell Stimulatory Factor (NKSF) or interleukin-12 (IL-12) is a heterodimeric cytokine of 70 kDa formed by a heavy chain of 40 kDa (p40) and a light chain of 35 kDa (p35). Although it was originally identified and purified from the supernatant of Epstein-Barr virus-transformed B cell lines, it has been shown that among peripheral blood cells $\text{NKSF}\text{IL-12}$ is predominantly produced by monocytes, with lower production by B cells and other accessory cells. The most powerful inducers of $\text{NKSF}\text{IL-12}$ production are bacteria, bacterial products and parasites. In addition to the biologically active p70 heterodimer, the cells producing $\text{NKSF}\text{IL-12}$ also secrete a large excess of monomeric p40, a molecule with no demonstrable biological activity. $\text{NKSF}\text{IL-12}$ is active on T lymphocytes and NK cells on which it induces production of lymphokines, enhancement of cytotoxic activity and mitogenic effects. $\text{NKSF}\text{IL-12}$ induces T and NK cells to produce IFN-γ and synergizes with other IFN-γ inducers in this effect. In vitro, and probably in vivo, $\text{NKSF}\text{IL-12}$ is required for optimal IFN-γ production. When human lymphocytes are stimulated with antigens in vitro, addition of exogenous $\text{NKSF}\text{IL-12}$ to the culture induces differentiation of T helper type 1 (Th1) cells, whereas neutralization of endogenous $\text{NKSF}\text{IL-12}$ with antibodies favors differentiation of Th2 cells. IFN-γ, a product of Th1 cells, enhances $\text{NKSF}\text{IL-12}$ production by mononuclear cells, whereas IL-10 and IL-4, products of Th2 cells, efficiently inhibit it. Therefore, $\text{NKSF}\text{IL-12}$ appears to be an important inducer of Th1 responses produced by accessory cells during early antigenic stimulation and its production is regulated by a positive feedback mechanism mediated by Th1 cells through IFN-γ and a negative one by Th2 cells through IL-10 and IL-4. The balance of IL-12 production versus IL-10 and IL-4 production early during an immune response might therefore be instrumental in determining Th1-type versus Th2-type immune responses. Because of this potential role of IL-12 during immune responses, our results demonstrating the impaired ability of HIV seropositive patients to produce $\text{NKSF}\text{IL-12}$ in response to bacterial stimulation suggest that this defect in $\text{NKSF}\text{IL-12}$ production might be a factor contributing to their immune depression.

Peptide growth factors have been implicated in three aspects of cartilage growth and metabolism; the induction of mesoderm and differentiation of a cartilaginous skeleton in the early embryo, the growth and differentiation of chondrocytes within the epiphyseal growth plates leading to endochondral calcification, and the processes of articular cartilage damage and repair. Three peptide growth factor classes have been strongly implicated in these processes, the fibroblast growth factor family (FGF), the insulin-like growth factors (IGFs) including insulin, and transforming growth factor-β (TGF-β) and related molecules. Each of these peptide groups are expressed in the early embryo. Basic FGF, TGF-β and the related activin have been shown to induce the appearance of mesoderm from primitive neuroectoderm. TGF-β and related bone morphometric proteins can induce the differentiation of cartilage from primitive mesenchyme, and together with basic FGF and IGFs promote cartilage growth. Each class of growth factor is expressed within the epiphyseal growth plate where their autocrine/paracrine interactions regulate the rate of chondrocyte proliferation, matrix protein synthesis and terminal differentiation and mineralization. Basic FGF may prove useful in articular cartilage repair, while basic FGF, IGFs and TGF-β are among a number of growth factors and cytokines that have been implicated in cartilage disease.

Cytokines and growth factors are involved in all important biological processes. Hence it is anticipated that they will be of importance in autoimmune disease. The pathogenesis of autoimmune diseases involves a number of stages, initiation, perpetuation and tissue damage, each of which involves different cell and molecular interactions. In this review, we will discuss an outline of the cytokine involvement in the various stages of autoimmune development, prior to focusing on the analysis of cytokines in rheumatoid arthritis. Cytokines exert their effect via high affinity cell surface receptors. Thus an understanding of cytokines involves the analysis of receptor expression, and also of cytokine inhibitors. Currently there is only adequate knowledge of these aspects in rheumatoid arthritis (RA), and as such the emphasis of this review is on RA. One of the major reasons for being interested in the role of cytokines in autoimmunity is to define possible therapeutic targets. There is now considerable evidence that TNFα is such a target in RA, and the effect of anti TNFα monoclonal antibody therapy in RA is discussed.

Insulin-like growth factor II (IGF-II) is a 67 amino acid polypeptide that belongs to the family of insulin-like peptides. The IGF-II gene is coupled to the insulin gene and paternally imprinted. Multiple IGF-II mRNAs with identical coding regions and 3′ untranslated regions (UTRs) but different 5′ UTRs are generated from 3 promoters. The transcripts are translationally discriminated and inactivated by a specific endonucleolytic cleavage in their 3′ UTR. These features may be important in the control of IGF-II production. IGF-II functions in an auto- and paracrine manner and binds to two types of receptors. The IGF-I receptor that is a tyrosine kinase and closely related with the insulin receptor and the IGF-II/mannose 6-phosphate ($\text{IGF-II}\text{Man 6-P}$) receptor that is identical with the cation-independent mannose 6-phosphate receptor. The mitogenic and metabolic actions of IGF-II are propagated by the IGF-I receptor. In contrast, the $\text{IGF-II}\text{Man 6-P}$ receptor, that target lysosomal enzymes from the Golgi apparatus or the plasma membrane to the lysosomes, mediates the rapid internalization and degradation of IGF-II.

IGF-II is expressed at high levels during foetal life and it is a major growth factor for the foetus in rodents. The developmental profiles and tissue distribution of the IGF-I and the maternally imprinted $\text{IGF-II}\text{Man 6-P}$ receptors both parallel that of IGF-II. In this scenario IGF-II promotes the growth of the embryo through the IGF-I receptor, whereas the $\text{IGF-II}\text{Man 6-P}$ receptor balance the activity by controlling the extracellular level of IGF-II.