Cytokines: Interleukins
147
An alternative method for determin-
ing
in vivo
roles of interleukins involves
neutralizing their biological activity with
speciFc antibodies, soluble receptors, and
other antagonists, that is, essentially pre-
venting the interaction of the interleukin
with its cognate receptors, also gener-
ates interesting results. To date, however,
the
abrogation
of
interleukin
activities
has mostly been carried out under con-
ditions in which pathological conditions
have been induced, for example, microbial
challenge, tissue injury, graft-versus-host
disease, or autoimmune disease. ±rom
these studies, for example, for IL-1, it
has been shown that neutralizing anti-
bodies suppress cell-mediated immunity
and increase susceptibility to pathogens
such
as
Listeria monocytogenes
.I
nt
h
i
s
case, the IL-1ra and soluble IL-1R can
also produce similar effects. Such work
indicates a protective role for IL-1. Inter-
estingly, supportive evidence for this has
been revealed by a series of recent Fndings
that members of certain virus families,
particularly the poxvirus family, encode
soluble homologs of interleukins or their
receptors, suggesting that some viruses
have evolved means of countering host-
defense mechanisms that would otherwise
inhibit their replication. ±or example, vac-
cinia and cowpox viruses encode a soluble
form of IL-1RII that can compete for IL-
1 binding to cell surface receptors and
thus reduce IL-1 actions. Besides this, the
IL-1RII homolog, cowpox virus has also
been found to encode for an inhibitor, a
serpin, of the IL-1ß converting enzyme,
and this too would be expected to in-
hibit an IL-1ß-driven immune response
from being mounted. The example of the
Epstein–Barr virus encoded homolog of
IL-10 has been previously discussed under
Sect. 4.10.
6
Pathophysiology and Disease Correlates
There are a large number of examples
of interleukins having pathophysiological
roles or disease correlates, regrettably far
too
many
to
be
covered
here,
which
may help understand the complex and
versatile nature of interleukins in health
and disease. Starting with IL-1, it is clear
that when produced at low levels it has
a
protective
role,
but
when
produced
at
high
levels,
which
spill
into
the
circulation, it produces a predominance of
proinflammatory effects that are correlated
with disease states such as hypotensive
shock and sepsis. High levels of IL-1
caninduceboneandcar
t
i
lageresorp
t
ion
and
degradation
and
IL-1ß
has
been
found in the synovial fluid and serum of
rheumatoid arthritis (RA) patients. Other
inflammatory cytokines such
as TN±
α
can also be found in RA synovial fluids.
Serum or plasma IL-6 levels can be greatly
increased by bacterial infections and result
in acute-phase responses. IL-8 levels are
raised in psoriasis scales. IL-10 levels can
be raised in malignant B-cell lymphomas
in AIDS patients.
Studies in transgenic mice where ex-
pression of interleukin genes is under the
control of constitutive promoters have also
contributed evidence of pathophysiologi-
cal effects. ±or example, IL-2 expression in
many body organs of transgenic mice leads
to baldness and interstitial pneumonia due
to an inflammatory inFltrate. In contrast,
IL-2 expression in the pancreas leads to a
lethal pancreatitis, but not diabetes. Con-
stitutive expression of IL-5, IL-6, and IL-7
can result in the expected hyperplasias,
that is, eosinophilia (IL-5), plasmacytosis
(IL-6), lymphocytosis (IL-7). However, the
site and control of IL-6 expression, for ex-
ample, is important in determining the
previous page 1467 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1469 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off