Biology Reference
In-Depth Information
found in the vicinity of the brush border membrane of the kidney or intestine.
Gastrin-17 has been shown to be one of the best substrates for homomeric meprin
Bwith a Kmof 1-7
10
5
M
1
s
1
(Villa et al.
2003
).
There is an increasing volume of data on meprin hydrolysis of immune-modulating
proteins such as the cytokines. The cytokine osteopontin was one of the first
cytokine substrates identified for the meprin B isoform (Bertenshaw et al.
2001
).
There is also some evidence that meprin
M; kcat/Kmvalues of 17-105
m
a
truncates several chemotactic cyto-
kines, such as MIP-1
, RANTES, and MCP-1 at their N-terminal end.
These truncations are predicted to lower the bioactivity of these cytokines
(Norman et al.
2003b
). Two members of the IL-1
a
, MIP-1
b
b
and proIL-18, have also been identified as meprin substrates. Both meprin A and
meprin B convert proIL-1
b
to a biologically active cytokine while only meprin B
has been shown thus far to convert proIL-18 to an active form (Herzog et al.
2005
,
2009
; Banerjee and Bond
2008
).
In vitro and in vivo studies imply that proIL-18 is a physiologically important
substrate for meprins A and B. Studies with meprin B in vitro indicate that the Km
for proIL-18 is 1.3
b
cytokine family, proIL-1
10
5
M
1
s
1
. This makes
proIL-18 one of the best substrates identified for meprins, and the kinetic values are
comparable to those for TACE and stromelysin for their physiological substrates.
The initial product of degradation of proIL-18 by meprin B results from hydrolysis
at an Asn-Asp bond (shown in Fig.
4.4
). This product is biologically active in a
cell-based system. Moreover, studies with meprin
M and the kcat/Km value is 52
m
knockout (KO) mice
with an experimental model of inflammatory bowel disease (IBD)
and
a
b
indicate that
active IL-18 is decreased in the serum of meprin
KO mice and increased the serum
b
of
KO mice compared to wild-type mice (Fig.
4.5
). These in vivo studies support
the contention that meprin
a
inacti-
vates the interleukin. Caspase-1, an intracellular protease, is known to be able to
generate biologically active IL-18. Our data indicate that meprin B is also able to
generate biologically active IL-18 in vivo, and we suggest that it hydrolyzes the
proform of IL-18 that is secreted from cells.
Meprins have also been implicated in regulating renal function in vivo by hydro-
lysis of B-type natriuretic peptide (BNP). BNP is expressed by a 108 amino acid
precursor that is subsequently processed into a biologically active 32 amino acid
product. The mature form of BNP is important for renal and cardiovascular
activates proIL-18 in vivo and that meprin
b
a
Fig. 4.4 Hydrolysis of proIL-18 by meprin B. The meprin B cleavage site is indicated, and the
nine amino acid sequence that was identified by MS/MS is
bolded
. Caspase-1 and putative PR3
cleavage sites are also indicated. The region of caspase-3 cleavage is
italicized
(Banerjee and Bond
2008
)
