TGF-beta signaling is involved in the regulation of proliferation, differentiation and survival/or apoptosis of many cells, including glioma cells. TGF-beta acts via specific receptors activating multiple intracellular pathways resulting in phosphorylation of receptor-regulated Smad2/3 proteins that associate with the common mediator, Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of many genes. Furthermore, TGF-beta -activated kinase-1 (TAK1) is a component of TGF-beta signaling and activates mitogen-activated protein kinase cascades. Negative regulation of TGF-beta /Smad signaling may occur through the inhibitory Smad6/7. Increased expression of TGF-beta 1-3 correlates with a degree of malignancy of human gliomas. TGF-beta may contribute to tumor pathogenesis by direct support of tumor growth, self-renewal of glioma initiating stem cells and inhibiting of anti-tumor immunity. Inhibitors of TGF-beta signaling reduce viability and invasion of gliomas in animal models and show promises as novel, potential anti-tumor therapeutics.
TGF-beta superfamily of cytokines bind to receptors at the cell surface, and recruit two type I receptors and two type II receptors forming a tetrameric complex. Activated TGF-beta superfamily receptors induce a series of phosphorylation cascade, from receptor phosphorylation to subsequent phosphorylation and activation of downstream signal transducer R-Smads (receptor-activated Smads). Phosphorylated R-Smads form a heteroligomeric (often trimeric) complex with Smad4 (Co-Smad). The Smad complex is imported into the nucleus and regulates the expression of target genes by direct binding to the target gene promoter and/or through the interaction with transcriptional cofactors in a cell-type-specific manner.
|Cytokine & Receptor Information|
Cytokines are a large group of proteins, peptides or glycoproteins that are secreted by specific cells of immune system. Cytokines are a category of signaling molecules that mediate and regulate immunity, inflammation and hematopoiesis. Cytokines are produced throughout the body by cells of diverse embryological origin. Cytokine is a general name; other names are defined based on their presumed function, cell of secretion, or target of action. For example, cytokines made by lymphocytes can also be referred to as lymphokines, while interleukins are made by one leukocyte and act on other leukocytes. And chemokines are cytokines with chemotactic activities.
Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action).
Several main groups of cytokines include: interleukins, chemokines, interferons, tumor necrosis factors (TNFs), colony-stimulating factors (CSFs), and TGF-beta superfamily members. Interleukins are a group of cytokines that were first seen to be expressed by leukocytes. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells. Chemokines are chemotactic cytokines with the ability to induce directed chemotaxis in nearby responsive cells. Stimulated by pro-inflammatory cytokines infected tissues release chemokines, and chemokine gradients induce leukocytes to move between endothelial cells and pass the basement membrane into the infected tissues. Interferons are cytokines which are made and released by the cells of most vertebrates in response to the presence of pathogens (such as viruses, bacteria, or parasites, or tumor cells). Interferons play critical role in host defense mechanisms. The tumor necrosis factor (TNF) superfamily of cytokines act through ligand-mediated trimerization, causing recruitment of several intracellular adaptors to activate multiple signal transduction pathways for cell survival, death, and differentiation. Colony-stimulating factors (CSFs), also called haematopoietic growth factors, are secreted glycoproteins which regulate bone marrow production of circulating red and white cells, and platelets.
An important part of Cytokines’ action on the immune system is to stimulate immune cell proliferation and differentiation. Cytokines involved in this function include interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; and other cytokines such as, interferon gamma, IL-3, IL-7 and colony-stimulating factor (GM-CSF).
Cytokines act on their target cells by binding specific membrane receptors. The receptors and their corresponding cytokines have been divided into several families based on their structure and activities. Type I cytokine receptors have certain conserved motifs in their extracellular amino-acid domain, and lack an intrinsic protein tyrosine kinase activity. Type II cytokine receptors are multimeric receptors composed of heterologous subunits, and are receptors mainly for interferons. The extracellular domains of type II cytokine receptors share structural similarities in their ligand-binding domain. Some cytokine receptors belong to the immunoglobulin superfamily, such as IL-1R alpha, IL-1R beta, IL-6R alpha, SCFR, c-kit, etc. Other cytokine receptors include TNF receptor family, chemokine receptors, and TGF-beta receptors.
Cytokines have been proved useful in immune-based therapies. For example, interferon-alpha, a cytokine with broad antiviral properties, has been proven to be useful in treating cancers, such as malignant melanoma. Cytokine therapy is not merely a tool of the future. In fact, several cytokine therapies are now routinely used by many people living with HIV.