118
Cytokines: Interleukins
rarely been possible to dissociate their desirable pharmacological activities from
their undesirable pharmacological activities, which often give rise to severe side
effects. In fact, many disease symptoms, for example, fever, hypotensive shock, have
been demonstrated to be strongly associated with the presence of endogenously
produced interleukins, and this is leading to clinical evaluation of several interleukin
antagonists in both acute and chronic diseases.
1
Background and Historical Perspective
From the beginning of the twentieth cen-
tury, there has been a growing realization
that many of the biological processes in
multicellular organisms are regulated by
extracellular factors. Together such fac-
tors constitute an elaborate, interactive
communication system that governs the
cellular and physiological responses at sev-
eral levels. In particular, the immune and
neuroendocrine systems of higher ani-
mals, such as mammals, are subject to
regulation by secreted factors that can act
both locally (paracrine action) and at a dis-
tance (endocrine action) on cells bearing
cognate receptors. The word ‘‘cytokine’’
was coined in 1974 by Dr Cohen to de-
scribe any soluble factor produced by both
lymphoid and nonlymphoid cells that exer-
cise speci±c effects in its target cells. Since
then, the de±nition of cytokine has become
restricted to nonendocrine, biologically ac-
tive, protein mediators involved in (1) cell
proliferation and thus tissue development
and repair and (2) cellular function, which
is required for the maintenance of homeo-
static and defense mechanisms. Cytokines
may
be
perceived
to
be
analogous
to
polypeptide hormones except, in contrast
to hormones, cytokines mainly act locally
rather than at a distance. However, in
many respects the distinction between cy-
tokines and hormones is blurred.
In today’s classi±cation, interferons, in-
terleukins, colony stimulating factors, and
polypeptide growth factors are considered
to belong to the cytokine superfamily. The
word ‘‘interleukin’’ was coined in 1979 at
the 2nd International Lymphokine Work-
shop in Ermatingen, Switzerland (quite
possibly interleukin was born from a cor-
ruption of Interlaken, another town in
Switzerland!), to apply to soluble mediators
produced by activated T lymphocytes that
acted in a paracrine fashion on ‘‘respon-
der’’ lymphocytes. However, the de±nition
of interleukin was quickly widened to in-
clude soluble mediators produced by a
wide variety of cell types that acted pri-
marily on lymphocytes and other cell types
within the immune system. Regrettably,
prior designation of some of the earlier
characterized cytokines, for example, in-
terferon gamma (IFN
γ
), has effectively
excluded them from the interleukin fam-
ily to which they truly belong, and the
inclusion/exclusion of newly discovered
cytokines to the interleukin family has of-
ten been fairly arbitrary.
Historically, the biological activities that
are now attributed to interleukins were
±rst uncovered as early as the 1940s. Then,
for example, a fever-inducing substance
isolated from ‘‘neutrophils’’ was called
granulocyte pyrogen
(GP); it had similar
properties to endogenous pyrogen (EP),
a substance isolated from the blood of
rabbits made febrile by the injection of
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