Transforming Growth Factor-β

TGF-β isoforms 1, 2, and 3 are part of a family of factors that influence growth and differentiation of cells with the capacity to both inhibit and/or stimulate growth. TGF-β was originally isolated as a factor that induced cellular transformation and anchorage-independent fibroblast cell line growth. Its many functional activities have been described. Intracellular signaling of TGF-β through its receptors has been reported. Although involved in normal cell regulation, abnormalities of the signaling of TGF-β have been associated with a number of diseases, including cancer. Mammalian genomes encode 33 polypeptides related to known TGF-β family polypeptides. These include, among others, the activins (activin and inhibin which are discussed later), bone morphogenetic proteins (BMPs 2 to 10), growth and differentiation factors (GDFs 1, 3, 5, 6, 7, 9, 10, 11, and 15), and nodal. Numerous studies have assessed roles for TGF-β in both positive and negative regulation of hematopoiesis and the immune system. Modulation of the effects of TGF-β has been explored to treat HSC defects and BM failure states including Fanconi anemia and myelofibrosis.

Inhibins (Activin and Inhibin)

Inhibins, belonging to the TGF-β family of polypeptides, are het erodimeric proteins that consist of an inhibin α and inhibin β chain, whereas activins are homodimers of inhibin/activin β chains. There are different inhibin chains (α and β) that have roles in a variety of developmental, physiologic, and disease states. Activin has enhancement activity for erythroid progenitor cells (e.g., burst-forming unit–erythroid [BFU-E]) in vitro and in vivo, whereas inhibin has suppressive effects on BFU-E in vitro and in vivo.

Bone Morphogenetic Protein

 BMPs, members of the TGF-β family, are secreted extracellular matrix (ECM) proteins that regulate a wide variety of development processes. They have been associated with a number of human disease states and in stem cell and organ formation, but their role in hematopoiesis has yet to be rigorously elucidated.

Tumor Necrosis Factor

 TNF was originally named for its capacity to cause the necrosis of selected tumors; it is derived from lymphocytes and macrophages and is distinguishable from lymphotoxin (LT). TNF is also a powerful cachexia-inducing factor associated with the devastating cachexic wasting side effects of the progression of cancer, and a pathogenetic role for TNF-α was proposed for the development of cachexia, arthritis, and autoimmunity due to tristetraprolin deficiency. When the gene encoding tristrapolin is disrupted in mice, the animals develop a severe syndrome of arthritis, autoimmunity, cachexia, dermatitis, and myeloid hyperplasia. The severe inflammatory syndrome which accompanies loss of tristetraprolin function in mice is in part the result of TNF-α messenger RNA (mRNA) stabilization and hypersecretion; TNF family members play numerous negative and positive regulatory roles in hematopoiesis—some modulated by ligand/receptor intracellular events that cause the release of a number of other cytokines, each with their different effector functions. There are large numbers of the TNF and TNF receptor superfamily members including, but not limited to, the receptors: CD40, FAS, KD30, 4-1BB, CD27, RANK, and the ligands (L): CD40L, FasL, OXr40L, Light, 4-1BBL, CD276, LT, Tweak, April, RANKL, and TRAIL/Apo2L.

Interferons

IFNs form another large family of related molecules. IFN were originally described as antiviral agents, but have since shown to have a large variety of actions that can have positive or negative effects on the hematopoietic and immune systems, through direct and indirect actions that are well documented. Indirect effects include induction of the release of other biologically active proteins. The inhibitory effects of IFN-α have been exploited to treat patients with MPNs.

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مواضيع ذات صلة

Specifics of Growth-Modulating Factors

Cytokines and Their Modifying Influences

Cancer Immunotherapy

Tumor Antigens

Mechanism Of Graft Rejection

Factors Influencing Allograft Rejection

Types of Graft Rejection

Histocompatibility Antigens

Disorders of Phagocytosis

Combined Immunodeficiencies (B and T Cells Defects)

Cellular Immunodeficiency (T Cell Defects)

Neuropathies