126
Cytokines: Interleukins
for example, LPS, phorbol myristate ac-
etate (PMA), increase protein kinase C
(PKC) activity, which in turn activates
the nuclear transcription factors, NF
κ
B
and AP-1 (composed of the protoonco-
gene products c-jun and c-fos). Binding
motifs for NF
κ
B and AP-1 are present in
the promoter regions of IL-1 genes. It is
probable that transcription of IL-1 genes is
regulated by activated NF
κ
BandAP
-1
,a
l
-
though presently it is not understood how
their transcription is differentially regu-
lated. Other factors such as intracellular
levels of cyclic AMP (cAMP) could be
important in this respect. Increased con-
centrations of cAMP have been found to
enhance IL-1ß expression, both at the tran-
scriptional and posttranscriptional level.
Interestingly, it is clear that IL-1
α
and ß can
themselves induce IL-1 gene expression,
probably utilizing the same PKC signal-
ing pathway and NF
κ
B/AP-1 transcription
factors as other IL-1 inducers. However, in
macrophages, LPS is by far the strongest
inducer of IL-1 gene expression.
In
contrast,
IL-2
gene
expression
is
dependent on mitogenic or antigenic stim-
ulation of T lymphocytes. Gene activation
requires at least three transcription factors,
AP-1, and two others designated NFAT-
1a
n
dN
F
I
L
-
2A
,w
h
i
c
ht
h
em
s
e
l
v
e
sa
r
e
subject to regulatory mechanisms. The
signaling pathway via PKC appears to
be involved in IL-2 gene induction. IL-
1, which also utilizes the PKC pathway
and is known to enhance IL-2 synthesis,
probably acts to augment/amplify the co-
operation of nuclear transcription factors
at the level of the IL-2 gene. The pro-
moter region of the IL-6 gene contains
the NF
κ
B and AP-1 binding motifs, sim-
ilar to those found in IL-1 genes, plus a
cAMP-responsive element (cRE).
It is known that other interleukin genes
are responsive to the same or similar
inducers that lead to IL-1 gene activa-
tion, for example, IL-6, IL-8, while others
are responsive to the same inducers that
lead to IL-2 gene activation, for example,
IL-3, IL-4, IL-5, IL-7, IL-9, IL-10, and IL-
13. Synthesis of the latter interleukins
is almost entirely restricted to T lympho-
cytes
,butregu
lat
ionatthetranscr
ipt
iona
l
level can determine which interleukins
are produced. Mature T-helper (h) CD4
+
lymphocytes, for example, can be sepa-
rated into two or more functional subsets.
The Th1 subset, which is responsible for
initiating responses against intracellular
pathogens and delayed-type hypersensi-
tivity, produces IL-2 and IFN
γ
,whe
rea
s
the Th2 subset, which preferentially in-
duces antibody-mediated responses, pro-
duces IL-4, IL-5, IL-6, IL-10, and IL-13.
Other
interleukins,
for
example,
IL-3,
and cytokines, for example, GM-CSF, tu-
m
o
rn
e
c
r
o
s
i
sf
a
c
t
o
ra
l
ph
a(TNF
α
)m
a
y
be produced by either subset (Table 3).
More immature Th lymphocytes, desig-
nated Th0, appear to be able to produce
an unrestricted range of interleukins and
cytokines. The mechanisms by which in-
terleukin genes are switched on and off in
Th lymphocytes are not fully understood,
but are partly dependent on differentia-
tion and maturation signals mediated by
other interleukins and cytokines, for exam-
ple, IL-12, IFN
γ
, and pathogenic triggers.
For example, allergens and certain para-
site antigens stimulate the development of
Th2 lymphocytes.
The production of interleukins is also
likely to be subject to posttranscriptional
and posttranslational controls. As men-
tioned earlier, the processing of IL-1
α
and
ß is complex, involving speci±c enzyme
cleavage of IL-1 31 kDa precursors and
transport of the mature, active 17.5 kDa IL-
1
α
and ß proteins through the cytoplasm
to cell membrane (neither IL-1 precursors
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