Early progenitor cells express receptors for multiple cytokines, but their expression becomes more restricted as cells become commit ted to a specific lineage.8 As a consequence of the broad range of cytokine receptor expression, early progenitors respond to combined growth factors, many of which show synergistic activity. The early acting cytokines include the interleukins IL-1 and IL-6, stem cell factor (SCF), FLT3 ligand, and several others, including granulocyte colony-stimulating factor (G-CSF) and thrombopoietin (TPO). IL-3 is important in directing the pluripotent stem cell toward the myelomonocytic lineage, giving rise to the mixed myeloid progenitor (CFU-GEMM). Subsequent stages leading to commitment- and lineage-restricted differentiation are governed by late-acting cytokines (Fig. 1).

Fig1. CYTOKINE REGULATION OF GRANULOCYTIC PROGENITORS. CFU-Baso, Colony-forming unit–basophil; CFU-E/Meg, colony forming unit–erythrocyte/megakaryocyte; CFU-Eo, colony-forming unit–eosinophil; CFU-G, colony-forming unit–granulocyte; CFU-GEMM, colony forming unit–granulocyte/erythrocyte/macrophage/megakaryocyte; CFU-GM, colony-forming unit–granulocyte/macrophage; CFU-M, colony-forming unit–macrophage; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; IL, interleukin; M-CSF, monocyte colony-stimulating factor; PHSC, pluripotent hematopoietic stem cell; SCF, stem cell factor.

The major cytokines that mediate neutrophil maturation are G-CSF and granulocyte–macrophage colony-stimulating factor (GM-CSF). G-CSF not only supports the survival and proliferation of developing myeloid cells at all stages of differentiation but also increases the functional activity of mature neutrophils. G-CSF binding to its receptor, G-CSFR, leads to homodimerization and signal activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and the Ras/mitogen-activated protein kinase (MAPK) pathways. The role of G-CSF as both an early- and late-acting cytokine is underscored by the successful use of G-CSF to mobilize early progenitors into the peripheral blood for stem cell collection and to speed neutrophil recovery following chemotherapy. Although the major role of G-CSF is thought to be induction of neutrophil proliferation and differentiation, the G-CSFR is also expressed on a wide range of cell types. In addition to myeloid progenitors and precursors at all stages of neutrophil differentiation, the G-CSFR is expressed on platelets, monocytes, and lymphocytes, as well as some nonhematopoietic tissues, including endothelium and placenta.

The importance of G-CSF in myeloid proliferation and differentiation has been studied in G-CSF–null and G-CSFR–null mice. Mice lacking G-CSF or G-CSFR have markedly decreased myeloid progenitors and impaired neutrophil production, with low circulating neutrophil counts. In addition, G-CSF–null mice have impaired neutrophil mobilization, and mature neutrophils from G-CSFR–null mice have increased susceptibility to apoptosis, supporting the role of the G-CSF pathway in sustaining the mobilization, survival, and function of mature neutrophils. Despite these abnormalities, G-CSF/ G-CSFR–knockout mice are still capable of some neutrophil pro duction, suggesting that there are alternative cytokine pathways that allow for granulocyte development.

GM-CSF also induces proliferation and differentiation of myeloid precursors. The GM-CSF receptor (GM-CSFR) is a heterodimeric protein composed of an α- and a β-subunit. The α-subunit binds GM-CSF. The β-subunit is shared by GM-CSFR and the receptors for IL-3, IL-5, and IL-6. The β-subunit does not bind ligand but is necessary for high-affinity ligand binding to the αβ-heterodimer of each receptor. Signaling through GM-CSFR activates both the JAK/ STAT pathway and the Ras/MAPK pathway. Of note, GM-CSF–null mice have no defect in hematopoiesis, whereas mice with null mutations in both G-CSF and GM-CSF have more profound neutropenia in the perinatal period but the same levels of neutrophils in adulthood as those of mice lacking G-CSF alone.

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مواضيع ذات صلة

Transcription Factors Regulating Myeloid Differentiation and Myeloid-Specific Gene Expression

Neutrophil Granules and Their Content Proteins

Stages of Neutrophil Differentiation

T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity

Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion

Allogeneic Banked Cells

Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies

Types of Cellular Immunotherapy

Adoptive Immunotherapy of Cancer

Therapeutic Manipulation of T-Cell-Mediated Immunity

T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure

T-Cell Memory