Cytokines: C:/CD DATA/all Collection notes/IMMUNOLOGY/cytokines - Doc - 1

Cytokines
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. Cytokines are the messengers of the immune system.
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.
These proteins assist in regulating the development of immune effector cells, and
some cytokines possess direct effector functions of their own.
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. 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.
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
C:\CD DATA\all collection notes\IMMUNOLOGY\cytokines.doc -1-
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.
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 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 lymphokines, and those secreted by monocytes and
macrophages, substances formerly known as monokines. 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.
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-molecularweight cytokines that affect
chemotaxis and other aspects of leukocyte behavior. These molecules play an
important role in the inflammatory response
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.
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.
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.
The TH1 subset is responsible for many cell-mediated functions (e.g., delayed-type
hypersensitivity and activation of TC cells) and for the production of opsonization-
promoting IgG antibodies (i.e. antibodies that bind to the high-affinity Fc receptors
of phagocytes and interact with the complement system). This subset is also
associated with the promotion of excessive inflammation and tissue injury.
The TH2 subset stimulates eosinophil activation and differentiation, provides help to
B cells, and promotes the production of relatively large amounts of IgM, IgE, and
noncomplement-activating IgG isotypes. The TH2 subset also supports allergic
reactions.
Cytokine Receptors
To exert their biological effects, cytokines must first bind to specific receptors
expressed on the membrane of responsive target cells. Because these receptors are
expressed by many types of cells, the cytokines can affect a diverse array of cells.
Cytokine Receptors Fall Within Five Families
Receptors for the various cytokines are quite diverse structurally,but almost all
belong to one of five families of receptor proteins ;
1.Immunoglobulin superfamily receptors
2. Class I cytokine receptor family (also known as the hematopoietin receptor
family)
3. Class II cytokine receptor family (also known as the interferon receptor
family)
4.TNF receptor family
5.Chemokine receptor family
General model of signal transduction mediated by most class I and class II cytokine
receptors. Binding of a cytokine induces dimerization of the receptor subunits, which leads
to the activation of receptor-subunit-associated JAK tyrosine kinases by reciprocal
phosphorylation. Subsequently, the activated JAKs phosphorylate various tyrosine
residues, resulting in the creation of docking sites for STATs on the receptor and the
activation of the one or more STAT transcription factors. The phosphorylated STATs
dimerize and translocate to the nucleus, where they activate transcription of specific genes.

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Cytokines

Cytokines are low-molecular weight regulatory proteins or glycoproteins secreted by

Cytokines regulate the intensity and duration of the immune response by

Binding of a given cytokine to responsive target cells generally stimulates increased

Cytokines exhibit the attributes of pleiotropy, redundancy, synergy, antagonism,

C:\CD DATA\all collection notes\IMMUNOLOGY\cytokines.doc -2-

Cytokines Have Numerous Biological Functions

Cytokines are involved in a staggeringly broad array of biological activities including

C:\CD DATA\all collection notes\IMMUNOLOGY\cytokines.doc -6-

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