Cytokines: Interleukins
133
a consequence activities can be shared
among
several
interleukins.
However,
since interleukins are in the main locally
produced
intercellular
mediators,
such
activities
are
dependent
on
the
cells
present in the vicinity of their release
expressing appropriate receptors, having
functional intracellular signaling pathways
and
having
transcriptionally
activatable
‘‘interleukin-responsive’’ genes.
For example, IL-6 is an inducer of acute-
phase proteins in hepatocytes and this has
proved to be a useful system for studying
the regulation of transcription of acute-
phase proteins. A nuclear transcription
factor, NF-IL-6, has been identi±ed in IL-6
stimulated hepatocytes that binds to the
promoter regions of acute-phase protein
genes. The NF-IL-6 transcription factor
is highly homologous to a liver-speci±c
transcription factor C/EBP, a member of
the so-called basic leucine-zipper family.
These leucine-zipper proteins are known
to bind to DNA as dimers through a
leucine-zipper structure that is required
for
dimerization
and
that
an
adjacent
basic region makes direct contact with
DNA. Serine phosphorylation of NF-IL-
6
is
required
to
activate
it
to
bind
to the IL-6-response elements in acute-
phase protein genes. Most of these genes
share
a
common
consensus
sequence
(CTGGGAA(T)), which also appears to
be
important
in
IL-6-dependent
acute-
phase protein gene activation. The acute-
phase proteins induced by IL-6 include
C-reactive protein (CRP), serum amyloid
A,
haptoglobulin,
α
1-antichymotrypsin,
±brinogen. These are largely restricted to
hepatocytes, but as IL-6 is active in many
different cell types, it is expected that IL-
6 stimulation will lead to the enhanced
transcription of a number of other genes,
for example,
c-jun, c-fos
.
Members of IL-8 family bind to G-
protein-coupled receptors. Binding of IL-8
to these receptors present on neutrophils
triggers a large rise in intracellular Ca
2
+
and activation of PKC, suggesting that
these
changes
are
involved
in
signal
transduction leading subsequently to neu-
trophil activation and the chemoattractant
response.
G-proteins, or
heterotrimeric
GTP-binding
regulatory
proteins,
have
been clearly implicated in signal trans-
duction; pertussis toxin (
Bordetella pertussis
islet-activating protein), which blocks the
activation of certain G-proteins, inhibits
the IL-8 stimulated chemoattractant re-
sponse.
The
activated
G-proteins
have
been found to activate phosphatidylinositol
phospholipase C and Ca
2
+
mobilization,
subsequent PKC activation, secretion of
granular enzymes, and activation of res-
piratory
burst,
and
the
generation
of
superoxide anion.
4
Biological Activities of Interleukins
There are now 29 recognized interleukins,
three colony stimulating factors (G-CSF,
GM-CSF, and M-CSF), and many more
cytokines, for example, TNF
α
,LIF
,OSM
,
CNTF, transforming growth factor ß (TGF-
β
), stem cell or steel factor and interferons
(IFN), to cite a noninclusive list, that can
affect the proliferation, differentiation, and
function of cells. With the number of
these biologically active mediators now
in the hundreds, the number of possi-
ble combinations is astronomic.
In vivo
,
it is probable that interleukins and other
cytokines form the basis of a complex in-
teractive communication network with the
overall cellular responses being dependent
on integrated assimilation of multiple sig-
nals.
In vitro
, it has been rarely possible to
previous page 1453 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1455 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off