Sepsis
consists
of
both
the
systemic
inflammatory
response
syndrome
(SIRS)
and
the
compensatory
anti-inflammatory
response
syndrome
(CARS).
How
these
differential
response
states
are
regulated
is
yet
to
be
fully
elucidated.
Tumour
necrosis
factor-alpha
(TNF)
is
one
of
the
principal
cytokines
involved
in
mediating
SIRS.
TNF
is
released
from
cells
by
tumour
necrosis
factor-alpha
converting
enzyme
(TACE),
this
enzyme
is
responsible
for
the
ectodomain
cleavage
of
a
number
of
other
substrates
relevant
to
inflammation
including
both
TNF
receptors
and
the
adhesion
molecule
L-selectin.
How
TACE
contributes
to,
and
functions
in,
SIRS
and
CARS
is
not
yet
known.
My
objective
was
to
investigate
TACE
activity
and
associated
substrate
shedding
in
monocytes,
specifically
how
the
enzyme
behaved
in
the
context
of
in
vitro
models
that
I
designed
to
induce
states
of
priming
and
tolerance.
I
then
obtained
in
vivo
samples
from
critically
ill
patients
to
determine
whether
there
were
similarities
between
the
TACE
activity
profiles
found
in
patient
cells,
and
volunteer
cells
placed
in
the
in
vitro
models.
My
aims
were:
1)
Determine
how
TACE
activity
profiles
were
altered
when
sequential
inflammatory
stimuli
were
utilised
in
a
two-hit
model
of
sepsis
designed
to
induce
states
of
priming
and
tolerance
and
2)
To
perform
a
clinical
study
to
investigate
TACE
behaviour
in
the
context
of
critical
illness.
I
successfully
refined
a
method
of
isolating
primary
monocytes
from
healthy
volunteers
and
patients
that
allowed
determination
of
TACE
activity
profiles.
Furthermore,
I
demonstrated
that
the
LPS-TACE
axis
was
reset
in
the
context
of
a
two-hit
LPS
model
and
in
sepsis.
I
found
evidence
of
differential
signalling
pathway
reprogramming
in
monocytes
taken
from
patients
with
infectious
and
non-infectious
SIRS.
Finally,
I
demonstrated
that
the
monocyte
TACE
response
to
LPS
is
dependent
on
cell
contact.
These
data
provide
new
insights
into
monocyte
inflammatory
function
during
the
immune
response.