Page 36 - Clinical Immunology_ Principles and Practice ( PDFDrive )

22 Part one Principles of Immune Response

Cytokines (Chapter 9) affect the growth and maintenance of a low level of proliferation of stem cells is required to avoid
pluripotent stem cells, as well as the development and differentia- exhaustion. The entry of stem cells into the cell cycle and the
tion of specific cell lineages. The effect of the cytokine can depend subsequent proliferation, as well as commitment to particular
on whether the cell has previously been or is concurrently being lineages, are controlled by cytokines and transcription factors.
stimulated by other cytokines. The stage of differentiation, as Data suggest that flt-3 ligand, c-kit ligand, and megakaryocyte
well as the presence or absence of the cytokine’s receptor on the growth and development factor all promote long-term stem cell
cell surface, also affects the cellular response. expansion. The combination of c-kit ligand, IL-3, and IL-6 causes
Stromal cells located within bone marrow and the thymus more rapid expansion but does not allow long-term extension
regulate hematopoietic and lymphoid cell growth and differ- of precursor cells. 11
entiation by releasing cytokines, such as interleukin 4 (IL-4), Several cytokines, alone or in combination, promote stem
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-6, -7, and -11; leukemia inhibitory factor (LIF); granulocyte cell growth (Table 2.3). Cytokine combinations are more effective
macrophage–colony-stimulating factor (GM-CSF); G-CSF; and at inducing stem cell growth compared with individual cytokines.
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stem cell factor (SCF). Stromal cells also participate in cell–cell IL-1 promotes stem cell growth by inducing bone marrow stromal
interactions with progenitors that express fibroblast growth factor cells to release additional cytokines and by synergistically stimulat-
1 (FGF-1) and FGF-2, which support HSC expansion. Stromal ing these cells in the presence of other cytokines. IL-3 promotes
cells form the intercellular matrix (e.g., fibronectin and collagen), the growth of hematopoietic progenitors. The effect is significantly
which binds to the selectin and integrin receptors present on enhanced by IL-6, IL-11, G-CSF, and SCF. Stromal cell–derived
hematopoietic and lymphoid progenitors. 10 IL-11 enhances IL-3–induced colony formation in 5-fluorouracil–
resistant stem cells. Cytokines secreted by stromal cells (e.g.,
Cytokines That Affect the Growth and Maintenance of IL-6, G-CSF, and SCF) exert their effects by shortening the G0
Pluripotent and Multipotent Stem Cells period in stem cells. IL-3 acts on cells after they have left G0.
Pluripotent stem cells can reconstitute cells of the hematopoietic IL-12 is unable to support the growth of primitive hematopoietic
and lymphoid lineages. Maintenance of pluripotent capacity is stem cells, either by itself or in conjunction with IL-11 or SCF.
mediated through factors that keep HSCs quiescent, including However, it acts in synergy with IL-3 and IL-11, or IL-3 and
c-kit, N-cadherin, osteopontin, transforming growth factor-β SCF, to enhance stem cell survival and growth.
(TGF-β), and Wnt. Factors that have a negative effect on qui- In some situations, a cytokine can enhance the growth of
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escence include Hedgehog and the notch ligands Delta and Jagged. hematopoietic and lymphoid cells, whereas in others the same
Because the stem cell pool is depleted as the progeny differentiate, cytokine can inhibit cell growth or enhance differentiation. LIF

TABLE 2.3 Cytokines Important for Hematopoietic Cell Growth and Differentiation

Cytokines Stem Cells thymocytes B Cells natural Killer (nK) Cells
Interleukin (IL)-1 Acts on stromal cells Differentiation
IL-2 Pleomorphic Proliferation Proliferation
IL-3 Proliferation
IL-4 Pleomorphic Promotes (low) Inhibits IL-2
Prevents (high)
IL-5 Proliferation/differentiation
IL-6 Shortens G0 Enhances stimulation Maintains potential Enhances IL-2
IL-7 Survival/proliferation Proliferation of pro- and Activation
pre-B cells
IL-10 Survival
IL-11 Oncostatin M Shortens G0 Maintains potential
IL-12 Survival Activation proliferation
IL-13 Activation/division of
mature B cells
IL-15 Proliferation Development/survival
IL- 21 Proliferation Expansion
Stem cell factor (SCF)/c-kit Survival Atrophy Maintains potential Expansion
G-CS Shortens G0 Maintains potential
FLt3 ligand Growth factor Increases proliferation Expansion
Stromal cell–derived factor Proliferation/regeneration Chemoattractant
(SDF)1-α
Leukemia inhibitory factor Proliferation Atrophy
(LIF)
Thrombopoietin Expansion/regulates
self-renewal
Tumor necrosis factor Proliferation: inhibits
(TNF)-α granulocytes
Transforming growth factor Inhibits growth enhanced
(TGF)-β granulocytes
Macrophage inflammatory Inhibits
protein (MIP)-1α
Nerve growth factor (NGF) Proliferation/differentiation Expansion