immune system. The consequence of cytokine binding to
receptors on the target cells is modulation of processes oc-
curring in the target cell. Cytokines can stimulate, inhibit,
upregulate, or downregulate depending on the particular
cytokines and cell types involved. Cytokines are similar
to hormones in that they act at sites (cell receptors) dif-
ferent from their sites of synthesis. There are many types
of cells that synthesize the various cytokines. Many of the
cytokines are
i.e., they exhibit multiple bio-
logical activities.
Simple classification of individual cytokines is difficult
because the function of a single cytokine can be different
depending on the target cell. Subcategories of cytokines
are defined, e.g., interleukins generally are cytokines pro-
duced by leukocytes, lymphokines are produced by lym-
phocytes, and monokines are produced by monocytes.
However, there are exceptions to these generalizations.
Other subcategories exist, e.g., interferons are historically
related to antiviral activities and growth factors are pre-
dominantly related to cellular growth.
Based on function, cytokines are divided into four cate-
gories. The first category contains the cytokines that medi-
ate natural immunity (IFN-a, IFN- /
, or type I interferons),
IL-1 and IL-
, and the chemokines of which more than 40
have been identified. The second category includes the cy-
tokines that regulate lymphocyte activation, growth, and
differentiation. Included in this group are IL-2, IL-4, and
TGF-/3. The third category includes cytokines that regulate
immune-mediated inflammation. These are IFN-y, TNF
lymphotoxin, IL-5, IL-10, IL-12, and MIF (migration in-
hibition factor). The fourth group includes cytokines that
stimulate hematopoiesis, e.g., IL-3, IL-7, and the colony-
stimulating factors, GM-CSF, M-CSF, and G-CSF.
Cytokines use a common signal transduction mecha-
nism to initiate the intracellular processes by which they
achieve their diverse biological effects. The biological ef-
fects are obtained through changes in the expression of
specific genes. Cytokine binding to a membrane receptor
results in the activation of a tyrosine kinase (a Janus kinase
of “Jak”). This in turn leads to intracellular phosphoryla-
tion of the receptor and prepares the receptor for binding of
a transcription factor. The transcription factors are mem-
bers of a group of signal transducer-activators of transcrip-
tion (Stat proteins). The specificity in cytokine signaling
is determined by a combination of receptor recognition
and specific recognition of particular Stat molecules by
different Jaks.
An annotated list of some of the cytokines involved in
immune system modulation is given in Table 35-4. The
rapid development of cytokine biology, however, guaran-
tees that such tables are likely to be incomplete the moment
that they are created and, more importantly, inaccurate
in some respects. Internet sites exist that update cytokine
information, e.g., the COPE (Cytokines Online Pathfinder
Encyclopedia) site at
Links to tables of synonyms, activity conversion units,
and other useful information are available from the latter
As protein molecules, cytokines can be classified most
simply based on their dominant secondary structures. Four
groups are defined on this basis. In the first group, the
structure is dominated by four a-helix bundles that are
arranged in pairs. The interferons and most interleukins
(IL-2 through IL-7, IL-9, IL-11, IL-13, and IL-15) are
members of this group. Interaction of these cytokines with
their receptors occurs via one of the helix pairs, the A-B
pair. An example, IFN-a2A, is shown in Figure 35-23A.
The second group contains molecules with short a
helix segments, /
-sheet motifs, and epidermal growth
factor (EGF)-like motifs. Included within this group are
the chemokines and members of the insulin-like cytokine
subfamily. The third group of cytokines is dominated by
long /
-sheet motifs. IL1
IL1-/6, TNF-a and TNF
- / 6
are members of this group. The last group is structurally
heterogeneous and contains domains similar to EGF-like
structures, immunoglobulin domains, and kringles and in
one, a proteinase-like region. (See figures in Chapter 36 for
examples of these motifs.) Examples of three-dimensional
structures representing group 1 (IFN-a2A and IL-4) and
3 are shown (Figure 35-24a-c).
The products of cytokine genes, like immunoglobulin
genes, can be varied by alternative splicing. Consequently,
investigation of cytokines and their actions is compli-
cated by this source of structural variation. Also, most
cytokines are glycosylated and secreted into the circula-
tion. Cytokine receptors on cells may indicate the state
of activation of the cytokine-stimulated cells. Investiga-
tion of cytokine receptors is aided by flow cytometry us-
ing fluorescence-labeled antibodies bound to the recep-
tors. Cytokine research is one of the most active areas of
immunological research.
35.12 Vaccines
Immunological memory, i.e., B cells and T cells that are
poised for rapid antibody formation and antigen destruc-
tion, provides the molecular basis for the successful use of
vaccines. In vaccination, the stimulation of B- and T-cell
clones leads to formation of antibodies to the foreign pro-
teins. Differentiation of some of the B cells that recognize
the antigen into memory cells provides the mechanisms
for resisting subsequent infections.
Weakened or killed organisms, or organisms with epi-
topes common to those of pathogens, can stimulate an
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