57
As elucidated in the previous sections of this chapter,
C1-INH is a serine protease inhibitor. However, C1-INH is
a unique serpin, because it can also form reversible, non-
covalent interactions at its N-terminal domain – that is,
its nonserpin domain. This ability is conferred because the
N-terminal domain is heavily glycosylated, which enables
multiple nonspecific interactions with a variety of substances.
One of these interactions was mentioned earlier in the
discussion of C1-INH’s inhibitory role in the complement
pathway. C1-INH binds reversibly with C3b in the alter-
native pathway of the complement system.
28,103,104,106
C1-INH is also capable of other important anti-inflam-
matory interactions between its N-terminal domain and
other cell proteins, cell surfaces, or lipids.
102,103
These include
bonds with:
•
Infectious agents, such as gram-negative bacteria
and their endotoxins
6,102-104
•
E- and P-selectin adhesion proteins on endothelial
cells
102-104
•
Extracellular matrix components such as type IV
collagen, laminin, entactin, and fibrin.
103
C1-INH can bind with gram-negative endotoxins, thus
limiting their ability to bind to receptors on macrophages,
which could otherwise cause endotoxic shock.
110
This inter-
action between the gram-negative bacteria and C1-INH is
believed to play an important role in controlling the mani-
festations of sepsis.
102,110,111
The interactions between C1-INH and the E- and P-selectins
on endothelial cells are believed to suppress leukocyte
adhesion.
102,103
The physiological significance for the interactions between
C1-INH and endothelial cells as well as between C1-INH
and extracellular matrix components is unknown. How-
ever, it has been postulated that these interactions may
help to concentrate C1-INH where it is needed most – at
the blood vessel walls.
102,103,110
The role of C1-INH as a downregulator of complement
activation and the inflammatory response has stimula-
ted animal and human research in the areas of ischemia-
reperfusion, septic shock, suppression of hyper-acute and
other forms of antibody-mediated transplant rejection,
and capillary leak syndrome.
6,26,102,103,110
Table 16 summa-
rizes the roles of C1-INH at its nonserpin domain. As new
science emerges, the understanding of the importance of
C1-INH and its numerous functions
in vivo
will continue to
expand.
MOA
7.2 Biochemical and Physiologic Roles of
C1-INH at the Nonserpin Domain
Category
Target of C1-INH
Nonserpin Domain
Interactions
Hypothesized
Biochemical Role
Proteins other than
C3b
Mediate inflammatory
serine proteases
response in the
alternative pathway of
the complement system
Extracellular matrix
Type IV collagen
Concentrate C1-INH at
proteins
Laminin
the inflammatory site
Entactin
Fibrin
Circulating cells
Macrophages
Unknown
Neutrophils
Vascular endothelial cells E-selectin
Regulate leukocyte
P-selectin
adhesion and
transmigration
Infectious agents
Gram-negative bacteria
Protection from sepsis
endotoxins
and endotoxin shock
Table 16 – C1-INH Binds Reversibly With
Target Substrates at its Nonserpin Domain
103,110
