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 membrane 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 affinities are so high, cytokines can mediate biological effects at picomolar concentrations.

A particular cytokine may bind to receptors on the membrane of the same cell that secreted it, exerting autocrine action; it may bind to receptors on a target cell in close proximity 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 regulate 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 secretion of antibodies or other cytokines. As described later, binding of a given cytokine to responsive target cells generally 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 interacting cells.

Cytokines exhibit the attributes of pleiotropy, redundancy, 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 similar 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

(a) Inducing stimulus

(a) Inducing stimulus

Cytokine-producing cell

Cytokine

Cytokine-producing cell

Cytokine

Autocrine action

Autocrine action

Paracrine action

Nearby cell

Paracrine action

Target cell

Biological effects

Receptor

Target cell

Circulation

Endocrine action

Nearby cell

Circulation

Distant cell

Endocrine action

Distant cell

Biological effects

FIGURE 12-1

(a) Overview of the induction and function of cytokines. (b) Most cytokines exhibit autocrine and/or paracrine action; fewer exhibit endocrine action.

effects of the individual cytokines. In some cases, cytokines exhibit antagonism; that is, the effects of one cytokine inhibit or offset the effects of another cytokine. Cascade induction occurs when the action of one cytokine on a target cell induces that cell to produce one or more other cytokines, which in turn may induce other target cells to produce other cytokines.

The term cytokine encompasses those cytokines secreted by lymphocytes, substances formerly known as lympho-kines, and those secreted by monocytes and macrophages, substances formerly known as monokines. Although these other two terms continue to be used, they are misleading because secretion of many lymphokines and monokines is not limited to lymphocytes and monocytes as these terms imply, but extends to a broad spectrum of cells and types. For this reason, the more inclusive term cytokine is preferred.

Many cytokines are referred to as interleukins, a name indicating that they are secreted by some leukocytes and act upon other leukocytes. Interleukins 1-25 have been identified. There is reason to suppose that still other cytokines will be discovered and that the interleukin group will expand further. Some cytokines are known by common names, including the interferons and tumor necrosis factors. Recently gaining prominence is yet another another subgroup of cytokines, the chemokines, a group of low-molecular-weight cytokines that affect chemotaxis and other aspects of leukocyte behavior. These molecules play an important role in the inflammatory response and are described in Chapter 15.

Because cytokines share many properties with hormones and growth factors, the distinction between these three classes of mediators is often blurred. All three are secreted soluble factors that elicit their biological effects at picomolar concentrations by binding to receptors on target cells. Growth factors tend to be produced constitutively, whereas cytokines and hormones are secreted in response to discrete stimuli, and secretion is short-lived, generally ranging from a few hours to a few days. Unlike hormones, which generally act long range in an endocrine fashion, most cytokines act over a short distance in an autocrine or paracrine fashion. In addition, most hormones are produced by specialized glands and tend to have a unique action on one or a few types of target cell. In contrast, cytokines are often produced by, and bind to, a variety of cells.

The activity of cytokines was first recognized in the mid-1960s, when supernatants derived from in vitro cultures of lymphocytes were found to contain factors that could regulate proliferation, differentiation, and maturation of allogeneic

Target Cell

Effect

CASCADE INDUCTION

PLEIOTROPY

PLEIOTROPY

Activated Th cells

Activated Th cells

REDUNDANCY

REDUNDANCY

Activated Th cells SYNERGY

Activated Th cells SYNERGY

Activated TH cells ANTAGONISM

IL-4

Target Cell

IL-4

Cytokines Synergy Antagonism

Activation

Proliferation

Differentiation

Proliferation

Proliferation

Mast cell

Activated TH cells ANTAGONISM

Activated TH cells

IFN-y

FIGURE 12-2

Activated TH cells

IFN-y

Mast cell

Proliferation

B cell

B cell

Induces class switch to IgE

B cell

B cell

Blocks class switch to IgE induced by IL-4

B cell

Activation

Proliferation

Differentiation

Proliferation

Proliferation

Proliferation

Induces class switch to IgE

Blocks class switch to IgE induced by IL-4

CASCADE INDUCTION

Activated TH cells

Activated TH cells

IFN-y

Macrophage

Macrophage

Activated TH cells

B cell

Activated TH cells

IFN-y, TNF, IL-2, and other cytokines

FIGURE 12-2

Cytokine attributes of (a) pleiotropy, redundancy, synergy (synergism), antagonism, and (b) cascade induction.

immune-system cells. Soon after, it was discovered that production of these factors by cultured lymphocytes was induced by activation with antigen or with nonspecific mitogens. Biochemical isolation and purification of cytokines was hampered because of their low concentration in culture super-

natants and the absence of well-defined assay systems for individual cytokines. A great advance was made with the development of gene-cloning techniques during the 1970s and 1980s, which made it possible to produce pure cytokines by expressing the protein from cloned genes. The discovery of

Cytokine bound to antibody coated onto well

Cytokine bound to antibody coated onto well

Add enzyme-conjugated secondary antibody

Add substrate and measure color

Add enzyme-conjugated secondary antibody

Add substrate and measure color

0.01 Li

0.1 1 10 100 Concentration of IL-12 (pg/ml)

FIGURE 12-3

ELISA assay of a cytokine. (a) The sample containing the cytokine of interest is captured by specific antibody (blue) coated onto wells of a microtiter plate. A second specific antibody (blue), conjugated to an enzyme (E) such as horseradish peroxidase, forms a sandwich with the captured cytokine, immobilizing the enzyme in the microtiter well. A chromogenic substrate (S) is added, and the enzyme generates a color whose intensity is proportional to the amount of cytokine bound to the capture antibody. The optical density of this color produced by the unknown is compared with values on an appropriately determined standard curve. (b) The standard curve shown here is for human interleukin 12 (IL-12). It is clear that this assay is sufficiently sensitive to detect as little as 1 picogram of IL-12. [Part (b) courtesy of R&D Systems.]

cell lines whose growth depended on the presence of a particular cytokine provided researchers with the first simple assay systems. The derivation of monoclonal antibodies specific for each of the more important cytokines has made it possible to develop rapid quantitative immunoassays for each of them (Figure 12-3).

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  • Kevin Herrmann
    What are biological prperties ofcytokines?
    8 years ago

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