There are many cytokines, including CSFs, ILs, and chemokines, which are enumerated as follows.

Colony-Stimulating Factors

Much of the original background on CSFs through the mid to late 1980s has been reviewed, but it is important to understand that the purification and respective cloning of the ligands and receptors of GM-CSF, G-CSF, IL-3, M-CSF, EPO, and TPO have led to the preclinical analyses of their biologic activities in vitro and in vivo, and the eventual evaluation of their effects in humans. For example, EPO has been used to enhance erythropoiesis and production of erythrocytes in humans under a variety of clinical scenarios, GM-CSF, G-CSF, and TPO have been used to accelerate production of myeloid cells, and G-CSF has also been used to mobilize HSC and HPC for eventual collection as autologous and allogeneic stem cell grafts.

Interleukins

The IL family of cytokines now includes IL-1 through IL-38/40, with the first IL, IL-1, purified to homogeneity in 1977. Examples of some of the actions of the ILs and the cell(s) that produce them are summarized in Table 1. ILs are placed in different families based on sequence homology, receptor similarities, and their functional activities. Some of the IL receptors are shown in Fig. 1. Many ILs, as do most members of the cytokine family, have redundant activities and have multiple effects on immune cells and hematopoiesis. Reviews on the IL-1, IL-2,101 IL-6, IL-10, IL-12, and IL-17 families present in-depth information on many of the known IL molecules. Examples of the hematopoietic actions of some of the ILs from our lab and others, such as IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 (also known as the chemokine CXCL8), IL-9, IL-10, IL-11, IL-12, IL-17, IL-18, IL-20, IL-21,IL-26, IL-31, IL-32, and IL-33, have been reported. The receptor for IL-33 is known as suppressor of tumorigenesis (ST2) which is primarily elevated during graft-versus-host disease (GVHD) and is a biomarker associated with a poor prognosis. IL-33 signaling is also associated with hematologic malignancies, autoimmune disorders, allergic inflammation, and gastrointestinal cancers. The ILs work in combination with other ILs, as well as other cytokines, to regulate hematopoiesis in an additive to synergistic fashion.

Table1. Interleukins

Fig1. CYTOKINE RECEPTORS. (A) Receptors for the interleukin (IL)-2 family (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21); (B) receptors for IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF); (C) receptors for IL-4 and IL-13; (D) IL-10 receptor family members (IL-10, IL-19, IL-20, IL-24, IL-26, IL-28, IL-29); (E) tumor necrosis factor (TNF)-α (TNFR1, TNFR2) and transforming growth factor (TGF)-β (TGF-βR1, TGF-βR2) receptors; (F) IL-12 receptor (IL-12 β1 plus IL-12Rβ3), IL-23 receptor (IL-12Rβ plus IL-23R); and (G) interferon (IFN)-α and IFN-β bind IFNAR1 plus IFNAR2, and IFN-β also binds R1 plus IFN-γ R2 heterodimers. (From Akdis M, Aab A, Altunbulakli C, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2016;138(4):984–1010, Fig. 1.)

Chemokines and Chemokine Receptors

Chemokines, originally considered chemotactic cytokines, are a large family of cytokines that usually signal through G protein–coupled heptahelical receptors (Table 2 and Fig. 2). There is redundancy within the chemokine family, with some chemokines binding multiple chemokine receptors and, in more rare occasions, nonchemokine receptors, and some chemokine receptors binding multiple chemokines. Fig. 3 diagrammatically denotes the many functions of chemokines and chemokine receptors. Chemokines can act as monomers but can form homodimers, heterodimers, and higher aggregates. Specific chemokines and their receptors have been implicated in various phases of HSC regulation. They can act as positive and negative regulators of HSC and HPC and have been implicated in the survival, proliferation, and mobilization of these cells. For example, IL-8/CXCL8, which acts through the chemokine receptors CXCR1 and CXCR2, has been implicated not only in the negative regulation of hematopoiesis, but CXCL8 and CXCR2 have been implicated in leukemia/MDS. Interestingly, DEK, a heterochromatin remodeling agent that has cytokine-like activity, can bind and signal through the chemokine receptor CXCR2 and can compete with IL-8/CXCL8, as well as macrophage inflammatory protein (MIP)-2, at the level of CXCR2. Extracellular DEK potently enhances cytokine-induced ex vivo expansion of mouse BM and human cord blood (CB) HSCs, plus has other effects. Another well-recognized chemokine and its receptor is SDF-1/CXCL12 and CXCR4, respectively. stromal cell-derived factor (SDF)-1/CXCL12 is involved in normal and leukemic HSC/ HPC survival, proliferation, chemotaxis, migration, and mobilization. SDF-1/CXCL12 also binds to CXCR7, but CXCR4 appears to be the main hematopoietic signaling receptor for SDF-1/CXCL12. Blocking of CXCR4 by the CXCR4 antagonist, AMD3100/plerixa for, has been used to induce the mobilization of peripheral blood HSC and HPC and to synergize with G-CSF in this mobilization. Chemokines are affected by a number of posttranslational modifications, including by DPP4, which is discussed later in this review. They are inducible by several different stimuli and are involved and are players in response to infection and inflammation. There are also viral genes that encode chemokine receptors. Chemokine receptors can also regulate infectivity to viruses. For example, individuals with specific mutations in CXCR5 are immune or less susceptible to infection with human immunodeficiency virus (HIV), but thus far only very few patients with HIV have been “cured” by allogeneic stem cell transplantation using donor cells from stem cell donors with this specific variant of mutated CXCR5.

Table2. Chemokines

Table2. Chemokines , cont’d

Fig2. MAMMALIAN CHEMOKINE RECEPTORS AND INTERACTIONS WITH CHEMOKINES AND KEY SECRETED CELL SURFACE AND PATHOGEN-ENCODED MOLECULES. (From Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J. 2018;285[16]:2944–2971, Fig. 1.)

Fig3. MULTIPLE CHEMOKINE/CHEMOKINE RECEPTOR FUNCTIONS. (From Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J. 2018;285[16]:2944–2971, Fig. 2.)

The complex network of cytokines and chemokines and their overlapping and diverse effects on a variety of cellular processes is truly incredible and goes beyond regulation of normal cells. Although redundant chemokine/chemokine receptor interactions are likely the body’s way to protect itself, this “protection” can elicit serious consequences. Many chemokines and their receptors are part of the triggered cytokine release syndrome (CRS), which represents a side effect following CAR-T-cell therapy and viral infections, such as that induced by SARS-Cov-2 during COVID-19 infections. These events lead to excessive elaboration of chemokines and other cytokines and their receptors, representing the “double-edged sword” discussed earlier in terms of health benefits and disease-related problems. Greater knowledge of the production and actions of chemokines, and their intracellular signaling cascades that are induced through chemokine and cytokine receptors, is crucial for future benefits for normal cell regulation and their modification and to dampen their adverse effects during disease.

Role of Nuclear Factor-κB in Cytokine and Chemokine Gene Regulation, Inflammation, Immunity, and Cancer

 NF-κB (nuclear factor kappa-light chain enhancer of activated B cells) is a protein complex controlling transcription of DNA, as well as cytokine production and cell survival. NF-κB is involved in cellular responses to stress, cytokines, irradiation, and bacterial or viral antigens. Aberrant NF-κB regulation is associated with cancer, inflammation, autoimmune diseases, septic shock, viral infection, and disordered development of immune cells. In an inactivated state, NF-κB is located in the cytosol with inhibitory protein IκBα. Through a variety of extracellular signals including cytokine and chemokine, the enzyme IκB kinases is activated, which then phosphorylate IκBα, resulting in ubiquitination dissociation of IκBα from NF-κB and degradation of IκBα by the proteasome. Activated NF-κB then translocates to the nucleus and binds to specific sequences of DNA termed response elements. The DNA/NF-κB complex recruits other proteins. There are numerous NF-κB target genes that include cytokines, chemokines, and their modulators (see https://www. bu.edu/nf-kb/gene-resources/target-genes/). Upstream signal trans duction of NF-κB activation has been described. Reviews and articles are reported on a role for NF-κB in cytokine gene regulation, chemokine gene transcription, and tumor growth,inflammation, cancer, multiple myeloma, and thrombosis. Many inhibitors of NF-κB signaling have been described. Overall, the impact of NF-κB on cytokines and chemokines and resultant physiologic and pathologic effects cannot be underestimated. With the multitude of cytokines and other factors that can influence NF-κB signaling, it is not at all surprising that NF-κB can regulate hematopoiesis. NF-κB has been shown to play an important role in the differentiation of HSCs and HPCs down both the myeloid and lymphoid pathways. The Rel/NF-κB transcription factors are mainly composed of five members (c-Rel, p65/RelA, RelB, NFKB1/p50, NFKB2/p52). P65 and p50 are ubiquitous proteins expressed in all hematopoietic lineages. However, the distinct expression pattern of the other Rel/ NF-κB factors in HPCs indicates their importance in HPC differentiation. Lymphocytes, monocytes, granulocytes, and erythrocytes express c-Rel. RelB is mostly expressed in DCs and lymphocytes. DCs, macrophages, and lymphocytes express p52. Using mouse knockout animal models, investigators have shown the importance of these factors in regulating hematopoietic differentiation.

Engineered Cytokines and Role of Cytokines and Other Reagents for Preclinical and Clinical Ex Vivo Expansion of Hematopoietic Stem Cells and Hematopoietic Progenitor Cells

Cytokines and/or chemokines when combined have additive to synergistic effects on proliferation of HPCs. This is especially so for the potent costimulating cytokines SCF (which acts through the c-kit receptor) and FL (which acts through the FL3 receptor). Efforts have been made to specifically engineer cytokines and chemokines for greater efficacy. This includes the GM-CSF/IL-3 fusion protein, PIXY32, which has been used in a clinical trial to promote hematopoietic recovery following chemotherapy-induced multilineage myelosuppression in patients with sarcoma, as well as IL-3/EPO, and IL-8/PF4174 fusion. These have had only limited clinical testing. By contrast, molecularly engineered forms of small molecule agonists of the thrombopietin receptor (eltrombopag and romiplostim) are currently used to treat patients with immune thrombocytopenic purpura as well as aplastic anemia.

Enhancement of ex vivo expansion of HSCs/HPCs for both preclinical and clinical use is an ongoing area of research. Current clinical trials on ex vivo expansion have been described. There are currently three sources of cells that have been used for clinical HCT. This includes BM, cytokine- and/or other reagent-induced mobilized peripheral blood, and umbilical cord blood. There have been a number of preclinical studies to expand numbers of CB HSCs and HPCs ex vivo. Some such as SR1, UM171, nicotinamide, prostaglandin (PGE)2 analog, and other reagents are currently in clinical trials. None of the ex vivo expansion procedures work without addition of combinations of cytokines such as SCF, TPO, and FL during the ex vivo culture period. Hence there is a need to add the reagent(s) of choice with SCF, TPO, and FL during the ex vivo culture period. Importantly, use of serum-free cultures and a short time of cell culture has benefits for potential use of the generated cells for clinical application. What is clear is that the most effective ex vivo expansion studies for clinical use is not yet known. Moreover, there are numerous other ex vivo expansion studies not yet tested clinically, and which of these may eventually be the procedure of choice for clinical use is as yet unknown.

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مواضيع ذات صلة

Transforming Growth Factor-β, Associated-Inhibin Family Members, Bone Morphogenic Protein, Tumor Necrosis Factor-α, and Interferons

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