Biomedical Engineering Reference
In-Depth Information
C. Anti-inflammatory/Immunomodulatory Activities
Secretory leukoprotease inhibitor expression is induced in LPS-treated macro-
phages, but IFN-
g
decreases SLPI expression (42). Secretory leukoprotease
inhibitor also has the ability to inhibit LPS-induced NF-
k
B activity in macro-
phages with resulting decreases in TNF-
a
and NO production. In further
studies, the ability of SLPI to inhibit LPS-induced NF-
k
B activation in U937
cells by preventing degradation of the key regulatory proteins,Interleukin-1
Receptor Associated Kinase (IRAK), I
k
B-
a
,andI
k
B-
b
, has been demon-
strated. Interestingly, in the presence of SLPI, the phosphorylated version of
I
k
B-
a
actually accumulates in the cell in addition to polyubiquitinated phos-
phorylated I
k
B-
a
. Oxidized SLPI treatment with LPS does not prevent degra-
dation of IRAK, I
k
B-
a
,andI
k
B-
b
indicating that the LPS inhibitory effects of
SLPI are dependent on its antiprotease activity (52).
In a model of acute lung injury, induced by intrapulmonary deposition
of IgG immune complexes in rats, prior administration of SLPI attenuates
pulmonary recruitment of neutrophils and decreases lung injury (53). Inves-
tigation of nuclear extracts from rat whole lungs revealed that deposition of
IgG immune complexes resulted in a significant increase in nuclear translo-
cation of NF-
k
B. However, administration of SLPI resulted in greatly
reduced NF-
k
B activation in whole lung samples, although downregulation
of NF-
k
B activation was not observed in alveolar macrophages (AMs)
isolated by BAL from these animals. Other studies have demonstrated
that SLPI increases LPS-induced expression of TGF
b
and IL-10 from
macrophages, as well as inducing HGF production by lung fibroblasts but
not by skin fibroblasts (54,55). Two recent studies have also indicated new
roles for SLPI in wound healing and apoptosis. The SLPI knockout (-
=
-)
mice have been shown to exhibit impaired cutaneous wound healing
with increased inflammation which is linked to increased elastase activity
and release of active TGF
b
, a major contributing factor to aberrant wound
repair (56). Secretory leukoprotease inhibitor has also been shown to bind to
proepithelin, an important anti-inflammatory protein, and prevent its con-
version to epithelin, a proinflammatory agent, by elastase (57). Release of
SLPI by macrophages during clearance of apoptotic cells also indicates a
possible role in inflammation resolution (58).
Another significant biological property of SLPI is its antiviral activity. Secre-
tory leukoprotease inhibitor has been shown to inhibit HIV infectivity of mono-
cytes by blocking viral DNA synthesis by a mechanism that does not involve
binding to HIV directly but is most likely due to interaction with the host cell
(59). In this study, SLPI was shown to bind a 55-kDa protein on the surface of
monocytes by which it may be mediating its antiviral properties. Subsequent inves-
tigations reveal that SLPI can bind the scramblase protein, which is involved in
membrane phospholipid movement and apoptosis (60). However, whether SLPI
can affect the activity of scramblase is currently unknown.
