150
Cytokines: Interleukins
IL-12 has been proposed as an antitumor
agent, but has proved to be quite toxic
when administered systemically to can-
cer patients.
In patients with chronic disease, the
presence of certain interleukins and their
potential
involvement
in
inflammatory
and degradative processes suggests that
countering their activities could produce
clinical beneFts. ±or example, IL-1 is fre-
quently found in the synovial fluids of
RA patients and is quite possibly associ-
ated with inflammatory symptoms. Thus,
intervention using anti-IL-1 antibodies, IL-
1ra, or soluble IL-1R is suggested as a
therapeutic approach for RA. ±or autoim-
mune diseases such as type 1 diabetes and
multiple sclerosis, a similar strategy em-
ploying IL-1 antagonists is also suggested.
These antagonists could additionally be po-
tentially useful in the treatment of acute
illness, for example, bacterial sepsis and
shock, as well as perhaps in other condi-
tions such as asthma and acute respiratory
distress syndrome (ARDS). So far, clin-
ical phase II trials of IL-1ra in sepsis
and RA patients have led to encouraging
results and, although IL-1ra was adminis-
tered in high doses, there were few, if any,
side effects.
In several types of hematological malig-
nancies, tumor cells secrete interleukins or
other cytokines that may act as autocrine
growth factors. ±or example, IL-2 and IL-7
maybep
roducedbylympho
idleukem
ia
cells,
IL-6
by
multiple
myeloma
cells
and IL-10 by B-lymphoma (e.g. Burkitt’s
lymphoma) cells. Such interleukin pro-
duction
therefore
suggests
a
case
for
investigating whether antagonists of these
interleukins would inhibit tumor cell pro-
liferation. There is as yet little clinical
work done in the cancer area with in-
terleukin antagonists, and it will be for
future clinical trials to determine if they
will be successful.
8
Concluding Remarks
Interleukin biology is highly complex due
to biochemical redundancy, pleiotropic ac-
tivities, and the numerous interactions
among interleukins themselves and with
other biological effector molecules. While
some
biological
activities
of
individual
interleukins shown
in vitro
can be demon-
strated
in vivo
, there remain questions
about types of expressing and responding
cells, sites, levels and duration of expres-
sion, developmental stages, and genetic
background. Advances in molecular ge-
netics, for example, knockout mice, have
provided means for identifying physiolog-
ical roles for some interleukins, but in
most instances it is still not certain that
such roles can be compensated for by
o
th
e
rin
t
e
r
l
eu
k
in
so
rc
y
t
o
k
in
e
s
,o
rh
ow
such roles are integrated within the host
intercellular communication network as
a whole. The present fragmentary evi-
dence for deFned physiological roles for
the majority of interleukins remains an
obstacle for translating the activities of
these powerful biological molecules into
clinically
useful
treatments
of
human
diseases.
Acknowledgments
6I am indebted to Miss Deborah Kirk for
the excellent typing of this chapter.
See
also
Bioorganic
Chemistry;
Medicinal Chemistry.
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