132
Cytokines: Interleukins
or more intracellular signaling pathways,
usually depending on the cell type. For
example,
IL-1
α
through
binding
to
IL-1R1
can
evoke
PKC
activity
in
T
cells and mouse NIH
3T3 fbroblasts,
whereas in human ±oreskin fbroblasts,
the cAMP-dependent protein kinase (PKA)
is
activated.
In
Th2
cells,
both
PKA
and
PKC
are
evoked
by
IL-1.
It
has
been
reported
that
IL-1
triggers
the
±ormation o± several second messengers,
including arachidonic acid metabolites via
phospholipase A
2
, prostaglandins via the
cyclooxygenase
pathway,
and
ceramide
via
sphingomyelin.
Ceramide
may
be
responsible ±or activating a serine kinase,
distinct
±rom
PKC,
which
is
involved
in phosphorylating the epidermal growth
±actor
(EGF)
receptor
and
causing
a
lowering o± the a±fnity o± this receptor
±or EGF.
As mentioned above, one o± the proteins
induced
by
IL-1
is
the
IL-2R
α
and
this, when expressed at the cell sur±ace
in combination with the two other IL-
2 receptor chains, IL-2Rß and IL-2R
γ
,
±orms the high-a±fnity receptor ±or IL-2.
In
contrast
to
IL-1RI, high-a±fnity
IL-
2R appears not to connect to signaling
pathways involving phosphatidyl inositol
hydrolysis, Ca
2
+
mobilization, PKC or
PKA. However, IL-2 stimulation is known
to result in tyrosine phosphorylation o±
several cytoplasmic proteins. It is now
known
that
the
intracellular
domains
o± IL-2Rß and IL-2R
γ
respectively, bind
via specifc tyrosine residues, the Janus
tyrosine
kinases
JAK1
and
JAK3.
The
JAKs
constitute
a
±amily
receptor-
activated kinases, which phosphorylate the
members o± a distinct class o± transcription
±actors known as
signal transducers and
activators of transcription
(
STATs
). Once
activated, STATs translocate to the nucleus
to activate transcription o± IL-2 responsive
genes.
Increased
expression
several
oncogenes,
including
c-myc,
c-myb,
c-
jun, c-fos
, and src-related protein tyrosine
kinase (PTK), which are probably involved
in cell proli±eration, are ±ound in IL-2
activated cells. Notably, other interleukin
and cytokine genes are also activated, but
their expression depends on the phenotype
o± the lymphoid cell. For example, the
Th-lymphocyte subsets Th1 and Th2 each
express a defned spectrum o± interleukins
and cytokines (Table 3).
The high-a±fnity receptors ±or IL-4, IL-7,
IL-9, IL-15, and IL-21 all share the IL-
2R
γ
chain, and there±ore bind JAK3 and
±unction in a similar way to the IL-2R. For
example, high-a±fnity IL-15R also requires
IL-2Rß and thus intracellular signaling
pathways are likely to be identical to those
triggered by IL-2. However, IL-15R
α
is
di±±erent ±rom IL-2R
α
and more widely
expressed, suggesting a broader activity
profle ±or IL-15. Most other high-a±fnity
interleukin receptors are composed o± two,
rather
than
three
chains – one
α
-a
n
d
one ß-chain. In the
case
o± IL-3 and
IL-5 receptors, which share a common ß-
chain, the latter is associated with JAK2,
which activates STAT5. Similarly, ±or IL-6
and IL-11 receptors, the ß-chain associates
primarily with JAK1, although other JAK
±amily kinases might also be involved in
signal transduction. In contrast, ±or IL-
10 receptors, and those ±or the related
interleukins IL-19, IL-20, IL-22, IL-24, IL-
26, IL-28, and IL-29, both
α
- and ß-chains
are associated with JAKs, in particular
with TYK2 and JAK1 and 2; a similar
association o± JAK2 and TYK2 with the
two receptor chains o± IL-12R and IL-
23R is also ±ound. It is evident there±ore
that due to the sharing o± JAKS and
STATs, the intracellular pathways ±rom
the majority o± interleukin receptors will
have
much
in
common,
and
that
as
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