okInes chapter 12 HE DEVELOPMENT OF AN EFFECTIVE IMMUNE response involves lymphoid cells, inflammatory cells, and hematopoietic cells. The complex inter- actions among these cells are mediated by a group of pro- ins collectively designated cytokines to denote their role in cell-to-cell communication. Cytokines are low-molecular- weight regulatory proteins or glycoproteins secreted by ite blood cells and various other cells in the body in response to a number of stimuli. These proteins assist in reg cytokines possess direct effector functions of their owl me ulating the development of immune effector cells, and some This chapter focuses on the biological activity of cyto- Class I Cytokine Receptors ines, the structure of cytokines and their receptors, signal transduction by cytokine receptors, the role of cytokine abnormalities in the pathogenesis of certain diseases, and a Properties of Cytokines therapeutic uses of cytokines or their receptors. The impor Cytokine Receptors tant role of cytokines in the inflammatory response is a Cytokine Antagonists described in Chapter 15 a Cytokine Secretion by TH1 and TH2 Subsets a Cytokine-Related Diseases Properties of Cytokines a Therapeutic Uses of Cytokines and Their Receptors Cytokines bind to specific receptors on the membrane of Cytokines in Hematopoiesis target cells, triggering signal-transduction pathways that ultimately alter gene expression in the target cells(figu 12-la). The susceptibility of the target cell to a particular cytokine is determined by the presence of specific mem- brane receptors. In general, the cytokines and their receptor exhibit very high affinity for each other, with dissociatio constants ranging from 10 to 10M. Because their af- finities are so high, cytokines can mediate biological effects at picomolar concentrations the activity of numerous cells involved in the immune a particular cytokine may bind to receptors on the mem- response. For example, cytokines produced by activated TH brane of the same cell that secreted it, exerting autocrine cells can influence the activity of B cells, Tc cells, natural ction; it may bind to receptors on a target cell in close prox- killer cells, macrophages, granulocytes, and hematopoietic imity to the producer cell, exerting paracrine action; in a few stem cells, thereby activating an entire network of interact- cases, it may bind to target cells in distant parts of the body exerting endocrine action( Figure 12-1b). Cytokines regu Cytokines exhibit the attributes of pleiotropy, redun- late the intensity and duration of the immune response by dancy, synergy, antagonism, and cascade induction, which stimulating or inhibiting the activation, proliferation, and/ permit them to regulate cellular activity in a coordinated or differentiation of various cells and by regulating the secre- interactive way(Figure 12-2). a given cytokine that has tion of antibodies or other cytokines. As described later, different biological effects on different target cells has a binding of a given cytokine to responsive target cells gener- pleiotropic action. Two or more cytokines that mediate sim- ally stimulates increased expression of cytokine receptors ilar functions are said to be redundant; redundancy makes it and secretion of other cytokines, which affect other target difficult to ascribe a particular activity to a single cytokine cells in turn. Thus, the cytokines secreted by even a small Cytokine synergism occurs when the combined effect of two number of lymphocytes activated by antigen can influence cytokines on cellular activity is greater than the additive■ Properties of Cytokines ■ Cytokine Receptors ■ Cytokine Antagonists ■ Cytokine Secretion by TH1 and TH2 Subsets ■ Cytokine-Related Diseases ■ Therapeutic Uses of Cytokines and Their Receptors ■ Cytokines in Hematopoiesis Class I Cytokine Receptors Cytokines T      response involves lymphoid cells, inflammatory cells, and hematopoietic cells. The complex inter￾actions among these cells are mediated by a group of pro￾teins collectively designated cytokinesto denote their role in cell-to-cell communication. Cytokines are low-molecular￾weight regulatory proteins or glycoproteins secreted by white blood cells and various other cells in the body in response to a number of stimuli. These proteins assist in reg￾ulating the development of immune effector cells, and some cytokines possess direct effector functions of their own. This chapter focuses on the biological activity of cyto￾kines, the structure of cytokines and their receptors, signal transduction by cytokine receptors, the role of cytokine abnormalities in the pathogenesis of certain diseases, and therapeutic uses of cytokines or their receptors. The impor￾tant role of cytokines in the inflammatory response is described in Chapter 15. Properties of Cytokines Cytokines bind to specific receptors on the membrane of target cells, triggering signal-transduction pathways that ultimately alter gene expression in the target cells (Figure 12-1a). The susceptibility of the target cell to a particular cytokine is determined by the presence of specific mem￾brane receptors. In general, the cytokines and their receptors exhibit very high affinity for each other, with dissociation constants ranging from 10–10 to 10–12 M. Because their af￾finities are so high, cytokines can mediate biological effects at picomolar concentrations. A particular cytokine may bind to receptors on the mem￾brane of the same cell that secreted it, exerting autocrine action; it may bind to receptors on a target cell in close prox￾imity to the producer cell, exerting paracrine action; in a few cases, it may bind to target cells in distant parts of the body, exerting endocrine action (Figure 12-1b). Cytokines regu￾late the intensity and duration of the immune response by stimulating or inhibiting the activation, proliferation, and/ or differentiation of various cells and by regulating the secre￾tion of antibodies or other cytokines. As described later, binding of a given cytokine to responsive target cells gener￾ally stimulates increased expression of cytokine receptors and secretion of other cytokines, which affect other target cells in turn. Thus, the cytokines secreted by even a small number of lymphocytes activated by antigen can influence the activity of numerous cells involved in the immune response. For example, cytokines produced by activated TH cells can influence the activity of B cells, TC cells, natural killer cells, macrophages, granulocytes, and hematopoietic stem cells, thereby activating an entire network of interact￾ing cells. Cytokines exhibit the attributes of pleiotropy, redun￾dancy, synergy, antagonism, and cascade induction, which permit them to regulate cellular activity in a coordinated, interactive way (Figure 12-2). A given cytokine that has different biological effects on different target cells has a pleiotropic action. Two or more cytokines that mediate sim￾ilar functions are said to be redundant; redundancy makes it difficult to ascribe a particular activity to a single cytokine. Cytokine synergism occurs when the combined effect of two cytokines on cellular activity is greater than the additive chapter 12