Biomedical Engineering Reference
In-Depth Information
cathepsin B, which normally obscures the active site. Subsequent mutagen-
esis experiments have revealed that mutation of His110 residue (which
anchors the occluding loop of cathepsin B to the main body of the enzyme)
alters the binding of cystatin C to cathepsin B from a two-step reaction to an
apparent one-step reaction (103).
B. Cystatins and Disease
A large body of research has centered on the role of cathepsins and cystatins
in tumor invasion, tumor growth, and angiogenesis (104,105). There is good
evidence to show that increased levels of cathepsin B are secreted from
tumor cells, which are not counterbalanced by increased cystatin expression
thus resulting in greater degradation of the extracellular matrix (105).
This degradation may also promote the formation of tumor-associated
angiogenesis (106).
Cystatins are also involved in nonlung tumor disease. Bronchoalveolar
lavage samples from patients with emphysema have demonstrated elevated
levels of cathepsin L activity which may have implications not only for
disruption of the extracellular matrix, but also degradation of soluble
defense proteins of the respiratory tract including SLPI and AAT (25).
Transgenic murine models, which overexpress IL-13 and IFN
g
, develop
emphysematous-like changes in the lungs (107,108). This overexpression
of IL-13 and IFN
g
is associated with increased expression of cathepsin B,
L, and S. However, small synthetic cathepsin inhibitors can significantly
decrease inflammation in this model, thus confirming that cathepsins do
play a significant role in IL-13-induced emphysema and tissue inflammation.
Elevated cathepsin activity has also recently been described in BAL samples
from CF patients and this can result in degradation of
b
-defensins with
concomitant loss of their antimicrobial activity (109). Therefore, increased
cathepsin activity and overwhelming of the cystatin screen in CF and COPD
may have consequences for lung tissue degradation, as well as predisposing
these individuals to infection.
C. Other Functions of Cystatins
Recent literature has indicated that members of the cystatin family may play
a role in modulating immune responses, particularly by macrophages.
Cystatins have been demonstrated to increase nitric oxide production from
IFN
g
-stimulated macrophages by a process that involves upregulation of
TNF-
a
and IL-10 production (110). Cystatins have also been shown to inhi-
bit growth of the pathogen P. gingivalis by a mechanism that does not
involve inhibition of P. gingivalis cysteine protease activity (111). In addi-
tion, peptides based on the protease-binding center of cystatin C can inhibit
growth of several bacterial species including group A streptococci (112).
Cystatins also exhibit antiviral properties by being able to inhibit replication
