Hematopoietic progenitors depend on a variety of cytokines to control their growth and differentiation. These include several different types of colony-stimulating factor (CSFs) and interleukins that each act on specific cell types to promote or inhibit particular types of responses. Detailed discussions of individual cytokines are presented in Chapter 10; for the present, we focus on general principles of cytokine action as illustrated in their effects on hematopoiesis.
In general terms, cytokines that influence hematopoiesis can be divided into three categories (see Table bellow):
(1) those that act on multipotent progenitors,
(2) those that act on lineage-committed progenitors, and
(3) those that have little effect by themselves but dramatically augment or inhibit the effects of the preceding cytokines.
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These divisions are not absolute, however, and many cytokines could appropriately be assigned to more than one category. For example, granulocyte monocyte colony-stimulating factor (GM-CSF) supports proliferation of both multipotential progenitors and precursors committed to monocyte formation. Similarly, thrombopoietin (TPO) supports growth and survival of HSCs but also promotes platelet formation. Certain cytokines can also substitute for one another: For example, large doses of either IL-3 or GM-CSF can sustain HSC proliferation in vitro. Thus, it is important to recognize that the effects of cytokines often are redundant or overlap one another. In addition, many cytokines that influence hematopoiesis also can affect the functions of fully differentiated blood cells. GM-CSF, for example, is an important regulator of the defensive activities of mature neutrophils. Similarly, interleukin-2 (IL-2) promotes not only the development of lymphocytes but also many of their protective functions.
In light of these complexities, it is best to view the cytokines as acting in a cooperative, interactive network. This makes it difficult (and sometimes misleading) to assign unique roles to any individual cytokine, particularly in the intact host. Nevertheless, hints to the predominant effects of cytokines have been obtained from experiments in which animals are genetically altered to lack a particular cytokine. In most cases, these studies show that the absence of one or several cytokines has minimal effect on blood cell development but often a more pronounced effect on mature leukocyte function. For example, mice deficient in GM-CSF show only minor decreases in myeloid cell production, but the neutrophils they produce are dysfunctional.
Although it was long believed that specific cytokines acted by inducing hematopoietic stem cells (HSCs) and progenitors to differentiate along a certain pathway, the weight of evidence currently favors another view. It now appears instead that each cell is intrinsically predisposed toward one lineage or another (apparently choosing among them at random) but is unable to proliferate, or even survive, unless the cytokines appropriate to that lineage are present. In other words, cytokines do not direct cells into a particular pathway but instead act as lineage-specific growth and survival factors. Thus, when progenitor cells are deprived of an essential cytokine, they not only cease growing but often dies actively committing suicide through a process called apoptosis (see later discussion). On the other hand, progenitors that have been genetically manipulated so that they cannot undergo apoptosis continue growing and differentiating along a particular lineage even when the cytokine is withdrawn, implying that the differentiative fate of each cell is intrinsically programmed. The concept that lineage commitment is a stochastic (ie, random) process and that one major function of cytokines is to promote survival, rather than induce differentiation, explains why so many cytokines seem to use so few signal transduction pathways, as will be described in the following section.
