Cytokines: Interleukins
123
C
C
N
N
2
2
3
1
6
6
1
3
9
8
7
5
4
11
10
12
4
5
7
8
10
9
11
12
Fig. 2
Stereo cartoon of IL-1ß. The twisted arrows represent ß-strands and they are
numbered sequentially from the N-terminal. The view is down the axis of the barrel formed by
six of the ß-strands. (Reprinted with permission from Priestle et al. (1988)
EMBO J
,
7
, 339.
Copyright EMBO/IRL Press Ltd, UK.)
2.2
Interleukin Genes
The fact that interleukin-like molecules
can be found in invertebrates indicates
that
interleukin
genes
probably
arose
very long ago (
>
500 million years). The
precise ancestry of interleukin genes is
not known, but it is clear that they have
been conserved throughout evolution from
an apparent ancient origin. The structures
of interleukin genes are complex, being
composed of several exons and introns
(cf
the
intronless
type
I
IFN
genes).
For
example,
the
human
IL-1ß
gene,
which
is
located
on
the
long
arm
of
chromosome
2,
contains
7
exons
and
6 introns. However, many of the other
interleukin genes share
a common 4-
exon-3-intron structure, for example, IL-2,
IL-4, IL-5, which is also found in the
GM-CSF and IFN
γ
genes
.Thegenefo
r
IL-6 has 5 exons and 4 introns, a feature
it
shares
with
the
G-CSF
gene.
The
interleukin genes are widely distributed
among human chromosomes (Table 2),
but
there
are
several
locations
where
interleukin families and their receptors
are clustered, for example, the genes for
IL-3, IL-4, IL-5, IL-9, IL-12p40, IL-13, GM-
CSF, monocyte-colony stimulating factor
(M-CSF) and its receptor are linked on
the long arm (q) of chromosome 5. The
equivalent site in the mouse genome is
located on chromosome 11.
The expression of interleukin genes is
dependent upon the activation of cellu-
lar transcription factors and the binding
of these to the response elements located
in the 5
0
flanking regions of the coding
DNA. The promoters and enhancers of
interleukin gene transcription have been
rather less studied than, for example, those
of the IFNß gene. For instance, while IL-
1
α
, IL-1ß, and IL-1ra genes are activated
by common inducers such as bacterial
lipopolysaccharide (LPS) and phorbol es-
ters, there are cellular mechanisms that
give rise to differential expression of their
respective mRNAs.
These
mechanisms
are poorly understood, but are probably
cell type speci±c. Inducers of IL-1 genes,
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