Cytokines Influence the Development of Many Cell Types
The cytokines form a family of relatively small, secreted signaling molecules (generally containing about 160–200 amino acids) that control growth and differentiation of specific types of cells. One large family of cytokines, the interleukins, are essential for proliferation and functioning of the T cells and antibody-producing B cells of the immune system (see Chapter 23). Another family of cytokines, the interferons, are produced and secreted by certain cell types following viral infection and act on nearby cells to induce enzymes that render those cells more resistant to viral infection.
Growth hormone (GH), as its name implies, is a 191-amino-acid protein that stimulates proliferation of many types of body cells; it is made and secreted by cells in the anterior pituitary gland in response to another hormone, growth hormone–releasing hormone, that is made by the part of the brain termed the hypothalamus. GH was one of the first protein drugs to be made by recombinant DNA; it is used clinically to treat growth disorders in children and GH deficiency in adults. The bovine version is used to increase milk production in dairy cows. During pregnancy, a related hormone, the cytokine prolactin, induces epithelial cells lining the immature ductules of the mammary gland to differentiate into the acinar cells that produce milk proteins and secrete them into the ducts.
GH and prolactin have three-dimensional structures very similar to those of several cytokines that induce the formation of important types of blood cells. All blood cells are derived from hematopoietic stem cells, which form a series of progenitor cells that then differentiate into the mature blood cells (see Figure 21-17). For instance, the cytokine granulocyte colony–stimulating factor (G-CSF) induces a granulocyte progenitor cell in the bone marrow to divide several times and then differentiate into granulocytes, the type of white blood cells that inactivate bacteria and other pathogens. A related cytokine, thrombopoietin, stimulates a different progenitor cell to divide and differentiate into megakaryocytes, huge cells that fragment into the platelets that are essential for blood clotting.
A structurally related cytokine, erythropoietin (Epo), triggers production of erythrocytes (red blood cells) by inducing the proliferation and differentiation of erythroid progenitor cells in the bone marrow (Figure 16-7). Erythropoietin is synthesized by certain kidney cells. A drop in blood oxygen, such as that caused by loss of blood from a large wound, signifies a lower than optimal level of erythrocytes, whose major function is to transport oxygen complexed to hemoglobin. The transcription factor HIF-1α is degraded in ambient oxygen levels. The kidney cells respond to low oxygen by preventing HIF-1α degradation; HIF-1α transcribes the erythropoietin gene, and the cells synthesize more erythropoietin and secrete it into the blood. As the level of erythropoietin rises, more and more erythroid progenitors are induced to divide and differentiate; each progenitor produces 30 to 50 erythrocytes in only a few days. In this way, the body can respond to the loss of blood by accelerating the production of erythrocytes.
FIGURE 16-7 Erythropoietin and formation of red blood cells (erythrocytes). Erythroid progenitor cells, called colony-forming units–erythroid (CFU-E), are derived from hematopoietic stem cells, which also give rise to progenitors of other blood cell types (see Figure 21-18). In the absence of erythropoietin (Epo), CFU-E cells undergo apoptosis (programmed cell death). Binding of Epo to its receptors on a CFU-E cell induces transcription of several genes whose encoded proteins prevent apoptosis, allowing the cell to survive. Other Epo-induced proteins trigger a developmental program of three to six terminal cell divisions, induction of hemoglobin and many other erythroid-important genes, reduction in cell and nuclear size, and finally, loss of the cell nucleus. If CFU-E cells are cultured with Epo in a semisolid medium (e.g., containing methylcellulose), daughter cells cannot move away, and thus each CFU-E cell produces a colony of 30–100 erythroid cells; hence its name. See M. Socolovsky et al., 2001, Blood 98:3261.
GH, prolactin, G-CSF, thrombopoietin, and Epo undoubtedly evolved from a common ancestral protein, since all of these cytokines have a similar tertiary structure consisting of four long conserved α helices folded together.
Both Epo and G-CSF are produced commercially by recombinant expression in cultured mammalian cells. Patients with kidney disease, especially those undergoing dialysis, frequently are anemic (have a low red blood cell count) and therefore are treated with recombinant Epo to boost red cell levels. Epo and G-CSF are used as adjuncts to certain cancer therapies because many cancer treatments affect the bone marrow and reduce production of red cells and granulocytes.