Thromb Haemost 2010; 104(05): 886-893
DOI: 10.1160/TH10-01-0073
Theme Issue Article
Schattauer GmbH

C1 inhibitor, a multi-functional serine protease inhibitor

Alvin E. Davis III
1  Immune Disease Institute, Program in Cellular and Molecular Medicine at Children’s Hospital Boston, Harvard Medical School, Boston, Masachusetts, USA
,
Fengxin Lu
1  Immune Disease Institute, Program in Cellular and Molecular Medicine at Children’s Hospital Boston, Harvard Medical School, Boston, Masachusetts, USA
,
Pedro Mejia
1  Immune Disease Institute, Program in Cellular and Molecular Medicine at Children’s Hospital Boston, Harvard Medical School, Boston, Masachusetts, USA
› Author Affiliations
Further Information

Publication History

Received: 28 January 2010

Accepted: 15 February 2010

Publication Date:
24 November 2017 (online)

Summary

C1 inhibitor (C1INH) is a serpin that regulates both complement and contact (kallikrein-kinin) system activation. It consists of a serpin domain that is highly homologous to other serpins and an amino terminal non-serpin mucin-like domain. Deficiency of C1INH results in hereditary angioedema, a disease characterised by episodes of angioedema of the skin or the mucosa of the gastrointestinal tract or the oropharynx. Although early data suggested that angioedema was mediated via complement system activation, the preponderance of the data indicate that bradykinin is the mediator. In the past few years, it has become apparent that C1INH has additional anti-inflammatory functions independent of protease inhibition. These include interactions with leukocytes that may result in enhanced phagocytosis, with endothelial cells via Eand P-selectins that interfere with leukocyte rolling and in turn results in suppression of transmigration of leukocytes across the endothelium, and interactions with extracellular matrix components that may serve to concentrate C1INH at sites of inflammation. In addition, C1INH suppresses gram negative sepsis and endotoxin shock, partly via direct interaction with endotoxin that interferes with its interaction with macrophages, thereby suppressing tumour necrosis factor-α and other inflammatory mediators. C1INH treatment improves outcome in a number of disease models, including sepsis and other bacterial infections, possibly malaria, ischaemia-reperfusion injury (intestinal, hepatic, muscle, cardiac, brain), hyper-acute transplant rejection, and other inflammatory disease models. Recent data suggest that this effectiveness is the result of mechanisms that do not require protease inhibition, in addition to both complement and contact system activation.