Colony-Stimulating Factors (CSFs) and Receptors Overview

Overview of Colony-Stimulating Factors

Colony-Stimulating Factors: Regulating Hematopoiesis and Beyond

Colony-stimulating factors (CSFs) encompass a group of signaling molecules with diverse functions in hematopoiesis and beyond. They include granulocyte CSF (G-CSF), macrophage CSF (M-CSF), granulocyte and macrophage CSF (GM-CSF), and multipotent colony-stimulating factor (IL-3). These factors play a vital role in promoting the proliferation and differentiation of hematopoietic stem cells at various developmental stages, making them essential for hematopoiesis. In a broader sense, cytokines stimulating hematopoiesis, such as erythropoietin, stem cell factor, leukemia inhibitory factor, and thrombopoietin, also fall under the category of CSFs due to their colony-stimulating activity. Moreover, CSFs exert heterogeneous effects on various mature cells, enhancing their functions.

Macrophage Colony-Stimulating Factor (M-CSF): Orchestrating Macrophage Function

Also known as CSF-1, M-CSF is primarily found in serum, urine, and other body fluids. It is produced by a range of cells, including monocyte-macrophages, lymphocytes, endothelial cells, fibroblasts, and epithelial cells. M-CSF stimulates the proliferation, differentiation, and survival of monocyte-macrophages, as well as enhances their function. It also plays a role in the formation of macrophage colonies from bone marrow hematopoietic cells. Moreover, M-CSF promotes the survival, proliferation, and activation of osteoclasts. Acting as a mediator in the inflammatory response, M-CSF enhances the ability of macrophages to eliminate tumor cells and microorganisms.

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF): Bridging Innate and Adaptive Immunity

Also referred to as CSF2, GM-CSF is produced by activated T cells, monocyte-macrophages, endothelial cells, fibroblasts, and other cell types. It primarily stimulates the growth and differentiation of precursor cells in the bone marrow, driving the differentiation of these cells into granulocytes and monocytes. GM-CSF promotes hematopoiesis and increases eosinophilia. Furthermore, GM-CSF has been found to lower serum cholesterol levels and can be used in the treatment of myeloid cell proliferation syndrome. Importantly, GM-CSF plays a key role in the development and maturation of dendritic cells (DCs) and the proliferation and activation of T cells, establishing a connection between innate and adaptive immune responses. Its administration in melanoma studies has shown increased numbers of immune cells in lymph nodes, resulting in sustained antitumor responses.

Granulocyte Colony-Stimulating Factor (G-CSF): Enhancing Granulocyte Function

Also known as CSF-3, G-CSF is a glycoprotein primarily produced by activated T cells, monocyte-macrophages, endothelial cells, and fibroblasts. G-CSF stimulates the differentiation and maturation of granulocyte precursor cells, enhancing the phagocytosis and killing functions of mature granulocytes while prolonging their survival time. Human and mouse G-CSF share considerable homology and exhibit cross-species biological activities. G-CSF induces differentiation and proliferation of neutrophil precursors in vitro, leading to the formation of mature granulocyte colonies. It also acts on fully mature neutrophils, prolonging their survival and promoting their phagocytosis and synthesis of alkaline phosphatase. Additionally, as a hematopoietic growth factor, G-CSF mobilizes cells from the bone marrow to the peripheral blood, aiding in myocardial perfusion, neovascularization, and the regeneration of injured myocardium. Clinically, G-CSF is widely used for the prevention and treatment of leukopenia induced by radiotherapy or chemotherapy, the treatment of bone marrow hematopoietic dysfunction, myelodysplastic syndrome, and the prevention of infectious complications associated with leukopenia.

The Link Between CSFs and Inflammatory Responses

Research suggests that CSFs, including GM-CSF and M-CSF, have a close association with pro-inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). CSFs form an integral part of the "CSF network" in inflammatory conditions. Furthermore, there is evidence connecting the IL-23-IL-17 pathway with both GM-CSF and G-CSF. Given the connection between these cytokine-mediated inflammatory responses and diseases such as rheumatoid arthritis, obesity, and cancer, CSFs may also contribute to the pathogenesis of various conditions. Notably, GM-CSF and M-CSF are expressed at higher levels in sites of inflammation and autoimmunity, such as the synovial fluid of rheumatoid arthritis patients.

Colony-Stimulating Factor Receptors: Roles and Signaling Pathways

1. GM-CSF Receptor: Orchestrating Cell Responses

Granulocyte and macrophage colony-stimulating factor (GM-CSF) receptor plays a crucial role in mediating the effects of GM-CSF, also known as colony-stimulating factor 2 (CSF2). GM-CSF is a cytokine composed of 127 amino acids, primarily produced by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and fibroblasts. Unlike granulocyte colony-stimulating factor, which specifically promotes neutrophil proliferation and maturation, GM-CSF affects a broader range of cell types, particularly macrophages and eosinophils. The GM-CSF receptor (GMR) consists of α and β receptors, both belonging to the type I cytokine receptor superfamily. The α receptor specifically binds to GM-CSF with low affinity, while the β receptor, upon binding with the α receptor, forms high-affinity aggregates. GMR activates signaling pathways, such as JAK-STAT and Ras-Raf-MAPK, through heterodimerization and subsequent phosphorylation events.

1. M-CSF Receptor: Regulating Macrophage Differentiation and Function

Macrophage colony-stimulating factor (M-CSF), also known as colony-stimulating factor 1 (CSF1), is a secreted cytokine that promotes the differentiation of hematopoietic stem cells into macrophages and related cell types. M-CSF's effects extend beyond the monocyte/macrophage lineage, as it influences early hematopoietic progenitor cell proliferation and impacts various physiological processes related to immunology, metabolism, fertility, and pregnancy. M-CSF receptor (CSF1R or M-CSF-R), belonging to the type III protein tyrosine kinase receptor family, is expressed on monocytes/macrophages, peritoneal exudate cells, plasmacytoid and conventional dendritic cells, and osteoclasts. Upon M-CSF binding, CSF1R undergoes autophosphorylation and activates downstream signaling pathways, including MAPK, JAK-STAT, and LPC-γ.

1. G-CSF Receptor: Regulation of Granulocyte Production and Cell Function

Granulocyte colony-stimulating factor (G-CSF), also known as colony-stimulating factor 3 (CSF3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells, which are subsequently released into the bloodstream. G-CSF, a critical growth factor, binds to its specific cell surface receptor, G-CSFR (CSF3R), triggering a complex signaling system that exerts various biological functions. These include regulating the proliferation, differentiation, and survival of granulocytes, promoting the secretion of vascular endothelial growth factor to enhance angiogenesis, mobilizing bone marrow stem cells to peripheral blood, and inducing immune tolerance of T cells in stem cell transplantation. CSF3R, a transmembrane protein with a type I cytokine receptor superfamily structure, consists of an extracellular region, a cytoplasmic region, and a transmembrane region. The G-CSF-CSF3R interaction leads to receptor dimerization and subsequent phosphorylation of tyrosine residues in the cytoplasmic region, initiating intracellular signaling through pathways such as JAK-STAT.

1. IL3 Receptor: Multi-Faceted Effects on Hematopoiesis

Interleukin 3 (IL3), also known as pluripotent colony-stimulating factor or mast cytokine, is predominantly produced by activated T cells and NK cells. Additionally, IL-3 can be produced by human endothelial cells activated by IL-1, mouse mast cells, and placental cells activated by IgE. IL-3's primary function is to promote the directional differentiation and proliferation of multipotent hematopoietic stem cells, leading to the production of various blood cell types. Furthermore, IL-3 regulates the growth, differentiation, and gene expression of mature cells, including the C-MYC and IL-2RA genes. The biological function of IL-3 is mediated by its specific receptor expressed on the cell membrane, known as the IL3 receptor (IL-3R). The IL-3R consists of two subunits, α and β. The α subunit, encoded by the CD123 gene, determines the specificity of IL-3 action and competes with ligand binding. The β subunit, also called KH97, is shared by IL-3, IL-5, and GM-CSF, and is responsible for intracellular signal transduction. IL-3R activates signaling pathways, including JAK-STAT, upon receptor dimerization and subsequent phosphorylation events.

Clinical Applications of Colony-Stimulating Factors

Colony-Stimulating Factors (CSFs) have significant clinical implications, particularly in the treatment and management of hematopoietic system diseases.

1. Treatment of Hematopoietic System Diseases: CSF family members, such as granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF), are widely utilized in the treatment of myelosuppression, agranulocytosis, and macrophage dysfunction. These factors promote the proliferation and differentiation of hematopoietic cells, enhance patients' immune function, and expedite bone marrow recovery and rehabilitation.
2. Management of Chemotherapy-Induced Bone Marrow Suppression: Chemotherapy drugs often lead to bone marrow function impairment, resulting in reduced blood cell count and compromised immune function. The application of CSF family factors aids in restoring bone marrow function, increasing blood cell production, improving immune system resilience, reducing infection risks, and enhancing the tolerance and efficacy of chemotherapy.
3. Bone Marrow Transplantation and Hematopoietic Stem Cell Transplantation: CSF family members also play a crucial role in bone marrow transplantation and hematopoietic stem cell transplantation. They promote the proliferation of donor bone marrow or stem cells, enhance hematopoietic function post-transplantation, and expedite recipient recovery and rehabilitation.
4. Treatment of Immune Diseases: Certain CSF family members, like tumor necrosis factor (TNF) inhibitors, are employed in the treatment of immune-related diseases such as rheumatoid arthritis and Crohn's disease. These factors regulate immune system function, reduce inflammation, and alleviate disease symptoms.

Summary of Colony Stimulating Factors

Collectively, colony-stimulating molecules are an important class of cytokines that are essential for the normal function of the hematopoietic system and immune regulation. Their research and clinical application help to understand the regulatory mechanism of hematopoietic process, and provide new strategies and methods for the treatment of related diseases.

References:

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[2] Schweizerhof, M. , St?Sser, S. , Kurejova, M. , Njoo, C. , Gangadharan, V. , & Agarwal, N. , et al. (2009). Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nature Medicine, 13(7), S96-S96.

[3] Weisbart, R. H. , Gasson, J. C. , & Golde, D. W. . (1989). Colony-stimulating factors and host defense. Annals of Internal Medicine, 110(4), 297.

[4] Andrew J. Fleetwood, Adrian Achuthan, John A. Hamilton,Colony Stimulating Factors (CSFs),Editor(s): Michael J.H. Ratcliffe,Encyclopedia of Immunobiology,Academic Press,2016,Page 586-596,ISBN9780080921525