IL
-
1
β
release is integral to
the innate
immune system.
The release of mature IL
-
1
β
depends on two regulated
events; (i) the
de
novo
induction of pro
-
IL
-
1
β
, generally via NF
κ
B
-
depend
ent
transduction pathways
and (ii)
the
assembly and
activation of
the
NLRP3 inflammasome
.
This latter step is reliant on active capase
-
1,
pannexin
-
1 and P2X
7
receptor
activation.
Pathogen associated molecular patterns in
Gram
-
positive and
Gram
-
negative bacteria
activate IL
-
1
β
release from immun
e cells via TLR2 and TLR4 receptors
respectively.
Here
,
we show that
pro
-
IL
-
1
β
and mature
IL
-
1
β
release from human monocytes
is
stimulated
by the TLR2 agonists
,
Pam
3
CSK4 or FSL
-
1
,
and the TLR4 agonist
,
LPS
,
in the absence of additional ATP
.
TLR2 agonists r
equired pannexin
-
1 and P2X
7
receptor activation
to stimulate IL
-
1
β
release
. By contrast, IL
-
1
β
release stimulated by the TLR4 agonist
,
LPS
,
is independent of both pannexin
-
1 and P2X
7
activation. In
the absence of exogenous ATP
,
P2X
7
activation requires
endogenous
ATP release, which occurs in some
cells via pannexin
-
1. In line with this
,
we found that LPS
-
stimulated human monocytes released relatively
low levels of ATP
,
whereas cells stimulated with TLR2 agonists released high levels of ATP. These finding
s
suggest that
,
in human monocytes
, TLR2 and TLR4 signalling both
induce pro
-
IL
-
1
β
expression
,
but
the
mechanism by which
they activate
caspase
-
1 diverges at the level
of
the pannexin
-
1/ATP/P2X
7
axis.