C1 inhibitor: Biologic activities that are independent of protease inhibition

Abstract

C1 inhibitor therapy improves outcome in several animal models of inflammatory disease. These include sepsis and gram negative endotoxin shock, vascular leak syndromes, hyperacute transplant rejection, and ischemia-reperfusion injury. Furthermore, some data suggest a beneficial effect in human inflammatory disease. In many inflammatory conditions, complement system activation plays a role in pathogenesis. The contact system also very likely is involved in mediation of damage in inflammatory disease. Therefore, the beneficial effect of C1 inhibitor has been assumed to result from inhibition of one or both of these systems. Over the past several years, several other potential anti-inflammatory effects of C1 inhibitor have been described. These effects do not appear to require protease inhibition and depend on non-covalent interactions with other proteins, cell surfaces or lipids. In the first, C1 inhibitor binds to a variety of extracellular matrix components including type IV collagen, laminin, entactin and fibrinogen. The biologic role of these reactions is unclear, but they may serve to concentrate C1 inhibitor at extravascular inflammatory sites. The second is a noncovalent interaction with C3b that results in inhibition of formation of the alternative pathway C3 convertase, a function analogous to that of factor H. The third is an interaction with E and P selectins on endothelial cells that is mediated by the Lewis x tetrasaccharides that are expressed on C1 inhibitor. These interactions result in suppression of leukocyte rolling and transmigration. The fourth interaction is the binding of C1 inhibitor to gram negative bacterial endotoxin that results in suppression of endotoxin shock by interference with the interaction of endotoxin with its receptor complex on macrophages. Lastly, C1 inhibitor binds directly to gram negative bacteria, which leads to suppression of the development of sepsis, as demonstrated in the cecal ligation and puncture model. These observations suggest that C1 inhibitor is a multi-faceted anti-inflammatory protein that exerts its effects through a variety of mechanisms including both protease inhibition and several different non-covalent interactions that are unrelated to protease inhibition.

The discovery and early validation of novel plasma biomarkers in mild-to-moderate Alzheimer's disease patients responding to treatment with rosiglitazone

“…It is therefore possible that this higher molecular weight band represents a complex of the two proteins, which is known to form in plasma (Davis et al 2007). A lowering in such a complex, seen in AD would be consistent with reduced inhibition of the classical complement pathway.…”

“…Complement C1 inhibitor is a regulator of the complement cascade system not only regulating key members of the cascade including complement C1r and complement C1s but also regulating other critical peripheral systems such as Factor XIIa, kallikrein and plasmin (Davis et al 2007). The levels of complement C1 inhibitor have previously been noted to be stimulated in AD brains, with increased inactivated levels noted in activated astrocytes and dystrophic neurites in areas surrounding AD plaque (Veerhuis et al 1996(Veerhuis et al , 1998.…”

Age-related macular degeneration and the complement system

“…SERPING1 also inhibits the lectin pathway (Kerr et al 2008), and has a range of non-specific anti-inflammatory activities (Davis et al 2007).…”

Functional Characterization of the Recombinant Human C1 Inhibitor Serpin Domain: Insights into Heparin Binding

“…More recently, reactivity toward the C1r-like protease (C1r-LP) has been reported (8). Over the past few years, several potential anti-inflammatory effects of C1 inhibitor, independent of its protease inhibitory activity, and involving noncovalent interactions with various proteins, cell surfaces, or lipids have been revealed (9). C1 inhibitor is a heavily glycosylated single-chain glycoprotein of 478 aa belonging to the SP inhibitor (serpin) superfamily (10).…”

“…The N-terminal extension of C1 inhibitor does not seem to affect protease inhibition (11,12), and its functional role remains elusive. However, interaction of C1 inhibitor with selectins on endothelial cells is known to be mediated by tetrasaccharides located in this area (9). Like other serpins, C1 inhibitor neutralizes its target proteases by presenting them a scissile peptide bond that matches their substrate specificity.…”