Cytokines Have Numerous Biological Functions

Although a variety of cells can secrete cytokines, the two principal producers are the TH cell and the macrophage. Cytokines released from these two cell types activate an entire network of interacting cells (Figure 12-5). Among the numerous physiologic responses that require cytokine involvement are development of cellular and humoral immune responses, induction of the inflammatory response, regulation of hematopoiesis, control of cellular proliferation and differentiation, and the healing of wounds. Although the immune response to a specific antigen may include the production of cytokines, it is important to remember that cytokines act in an antigen-nonspecific manner. That is, they affect whatever cells they encounter that bear appropriate receptors and are in a physiological state that allows them to respond.

Cytokines are involved in a staggeringly broad array of biological activities including innate immunity, adaptive immunity, inflammation, and hematopoiesis. Altogether, the total number of proteins with cytokine activity easily exceeds 100 and research continues to uncover new ones. Table 12-1 summarizes the activities of some cytokines and places them into functional groups. An expanded list of cytokines can be found in the Appendix. It should be kept in mind that most of the listed functions have been identified from analysis of

Functional groups of selected cytokines1

Cytokine*

Secreted by*

Targets and effects

SOME CYTOKINES OF INNATE IMMUNITY

Interleukin 1 (IL-1)

Tumor Necrosis Factor-a (TNF-a)

Interleukin 12 (IL-12) Interleukin 6 (IL-6)

Interferon a (IFN-a)

(This is a family of molecules)

Interferon p (IFN-p)

Monocytes, macrophages, endothelial cells, epithelial cells

Macrophages

Macrophages, dendritic cells Macrophages, endothelial cells

Macrophages

Fibroblasts

SOME CYTOKINES OF ADAPTIVE IMMUNITY

Interleukin 2 (IL-2)

Interleukin 4 (IL-4) Interleukin 5 (IL-5) Interleukin 25 (IL-25) Transforming growth factor p (TGF-p)

Interferon 7 (IFN-7)

T cells

Th2 cells; mast cells Th2 cells Unknown

T cells, macrophages, other cell types

Th1 cells; CD8+ cells; NK cells

Vasculature (inflammation); hypothalamus (fever);

l iver (induction of acute phase proteins)

Vasculature (inflammation); liver (induction of acute phase proteins); loss of muscle, body fat (cachexia); induction of death in many cell types; neutrophil activation

NK cells; influences adaptive immunity (promotes TH1 subset)

Liver (induces acute phase proteins); influences adaptive immunity (proliferation and antibody secretion of B cell lineage)

Induces an antiviral state in most nucleated cells; increases MHC class I expression; activates NK cells

Induces an antiviral state in most nucleated cells; increases MHC class I expression; activates NK cells

T-cell proliferation; can promote AICD. NK cell activation and proliferation; B-cell proliferation Promotes TH2 differentiation; isotype switch to IgE Eosinophil activation and generation Induces secretion of TH2 cytokine profile Inhibits T-cell proliferation and effector functions; inhibits B-cell proliferation; promotes isotype switch to IgE; inhibits macrophages Activates macrophages; increases expression MHC class I and class II molecules; increases antigen presentation

Many cytokines play roles in more than one functional category.

*Only the major cell types providing cytokines for the indicated activity are listed; other cell types may also have the capacity to synthesize the given cytokine. **Also note that activated cells generally secrete greater amounts of cytokine than unactivated cells.

the effects of recombinant cytokines, often at nonphysiologic concentrations, added individually to in vitro systems. In vivo, however, cytokines rarely, if ever, act alone. Instead, a target cell is exposed to a milieu containing a mixture of cytokines, whose combined synergistic or antagonistic effects can have very different consequences. In addition, cytokines often induce the synthesis of other cytokines, resulting in cascades of activity.

The nonspecificity of cytokines seemingly conflicts with the established specificity of the immune system. What keeps the nonspecific cytokines from activating cells in a nonspecific fashion during the immune response? One way in which specificity is maintained is by careful regulation of the expression of cytokine receptors on cells. Often cytokine receptors are expressed on a cell only after that cell has interacted with antigen. In this way cytokine activation is limited to antigen-activated lymphocytes. Another means of maintaining specificity may be a requirement for direct interaction between the cytokine-producing cell and the target cell to trigger cytokine secretion, thus ensuring that effective concentrations of the cytokine are released only in the vicinity of the intended target. In the case of the TH cell, a major producer of cytokines, close cellular interaction occurs when the T-cell receptor recognizes an antigen-MHC complex on an appropriate antigen-presenting cell, such as a macrophage, dendritic cell, or B lymphocyte. Cytokines secreted at the junction of these interacting cells reach high enough local concentrations to affect the target APC but not more distant cells. In addition, the half-life of cytokines in the bloodstream or other extracellular fluids into which they are secreted is usually very short, ensuring that they act for only a limited period of time and thus over a short distance.

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