Cytokines: Interleukins
131
included in the Ig superfamily rather than
the hematopoietin superfamily. They have
more recently been classiFed with Toll-like
receptors, a family of 10 proteins involved
in regulating innate immunity. The larger
80-kDa IL-1RI has an intracellular domain
(217 amino acids) of sufFcient size to
effect signal transduction, whereas the
smaller 68-kDa IL-1RII has only a short
intracellular C-terminal tail and is probably
not able to act as a signal transducer
on its own. There is a large body of
evidence
demonstrating
that
IL-1RI
is
functional and is required to mediate IL-1
activities, but the biological signiFcance
of
the
‘‘incomplete’’
IL-1RII
is
poorly
understood. Recent evidence suggests IL-
1RII acts as an inactive ‘‘decoy’’ receptor
to bind excess IL-1ß. Expression of IL-
1RI is inducible or highly regulated and
this probably to some extent controls the
responsiveness to IL-1
α
and ß, although it
is known that low (5%) receptor occupancy
is sufFcient to trigger intracellular events.
Both IL-1
α
and ß bind with similar afFnity
to IL-1RI and their binding is competitively
inhibited by IL-1ra. Shortly after binding,
the receptor-ligand complex is internalized
and may be translocated to the nucleus.
The
receptors
for
IL-8
and
related
molecules
belong
to
a
separate
re-
ceptor
family,
that
of
the
so-called
G-protein-coupled receptor superfamily.
These receptors contain seven membrane-
spanning helices that couple to guanine
nucleotide binding proteins (G-proteins).
±or IL-8, there are two distinct receptors,
type I and type II (or type A and B), which
are about 74% related in amino acids. It is
probable that IL-8 and other members of
the c-x-c subgroup of chemokines utilize
these two receptors, whereas the c-c sub-
group (includes MCP-1, RANTES, MIP-
1
α
/ß) have recently been shown to bind
to another G protein–coupled receptor,
which has approximately 33% homology
to the IL-8 receptors.
3.2
Intracellular Signaling Pathways
None of the interleukin receptors has an
integral protein kinase. However, it is now
known that they are associated through
their intracellular domains, either directly
or indirectly via adaptor proteins, with
‘‘nonreceptor’’ protein kinases to enable
signal transmission to occur. ±or exam-
ple, the intracellular domain of IL-1RI
interacts with an adaptor molecule known
as MyD88, which in turn couples to an
‘‘interleukin-1 receptor associated kinase’’
(IRAK). This serine kinase phoshorylates a
signal transducer belonging to the tumor
necrosis factor receptor associated factor
(TRA±) family and this leads to the ac-
tivation of nuclear transcription factors,
such as AP-1 (jun/fos) and N±
κ
B; these
in turn activate IL-1 responsive genes. It
is known that IL-1 can potentially induce
the expression of a whole catalog of genes
ranging from those of other interleukins
and cytokines, for example, IL-2 to IL-8,
GM-CS±, TN±
α
and its own family genes,
that is, IL-1
α
/ß and IL-1ra to a wide vari-
ety of enzymes (for example, manganous
superoxide dismutase, cyclooxygenase, tis-
sue plasminogen activator, collagenase),
oncogenes (
c-fos, c-jun, c-myc
), cell ad-
hesion molecules (intercellular adhesion
molecule-1 (ICAM-1), vascular cell adhe-
sion molecule-1 (VCAM-1)) and the 25-kDa
IL-2 receptor chain, IL-2R
α
(tac antigen).
Many of these proteins are only speciFcally
induced in certain cell types. However,
mechanisms underlying such differential
expression of IL-1 inducible genes remain
not well understood.
It
appears
probable
that
individual
interleukin receptors can be coupled to one
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