Hematopoietic cytokines

Abstract

The production of hematopoietic cells is under the tight control of a group of hematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating the various responses-survival, proliferation, differentiation commitment, maturation, and functional activation. Individual cytokines can be lineage specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency hematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. In this little review, discussion will be restricted to those cytokines well established as influencing the production of hematopoietic cells and will exclude newer candidate regulators and those active on lymphoid cells. As requested, this account will describe the cytokines in a historical manner, using a sequential format of discovery, understanding, validation, and puzzlement, a sequence that reflects the evolving views on these cytokines over the past 50 years.

Figure 1

Three types of action of hematopoietic cytokines. (A) Lineage restricted. (B) Action on multiple lineages; broken line shows actions only at high concentrations. (C) Sequential actions; SCF acts on stem and early erythroid progenitors, while EPO acts on more mature precursors. The notion of sequential actions was later found to be incorrect.

Figure 2

Varying tissue origin of hematopoietic cytokines. (A) EPO is mainly a product of kidney tissue. (B) GM-CSF is a product of multiple tissues and cell types. (C) M-CSF, CSF-1 can be a humoral factor and the product of many tissues or a membrane-displayed factor on local stromal cells.

Figure 3

Hematopoietic cytokines are polyfunctional. Hematopoietic cytokines such as G-CSF are not simply mandatory proliferative stimuli but also act on cell survival, differentiation commitment, maturation induction, and the functional stimulation of mature cells.

Figure 4

The importance of a hematopoietic cytokine such as G-CSF can be validated in several ways. (A) By injecting G-CSF to elevate neutrophil levels and (B) by deleting the gene, a procedure resulting in low neutrophil levels and poor neutrophil responses to challenge infections.

Figure 5

The confusing nature of some hematopoietic cytokines as illustrated by LIF. LIF was isolated as a factor active in suppressing a myeloid leukemic cell line. However, it has obvious additional actions on multiple tissues and is essential for blastocyst implantation and successful pregnancy.