Interaction of <sup>125</sup>I‐labelled complement subcomponents Cr and Cs with protease inhibitors in plasma

Sim, Robert B.; Reboul, Anne; Arlaud, Gérard J.; Villiers, Christian; Colomb, Maurice G.

doi:10.1016/0014-5793(79)80063-0

Cited by 144 publications

(61 citation statements)

References 14 publications

(1 reference statement)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Protease inhibition clearly is the major biologic role of C1 inhibitor. It is the only protease inhibitor that inactivates C1r and C1s (Sim et al, 1979;Ziccardi, 1981), the initial proteases activated via the classical complement pathway. It also regulates lectin pathway activation via inhibition of MASP2 (Ambrus et al, 2003;Matsushita et al, 2000a;Matsushita et al, 2000b;Matsushita et al, 2001), the initial protease activated in this pathway.…”

Section: Introductionmentioning

confidence: 99%

C1 inhibitor: Biologic activities that are independent of protease inhibition

Davis

Cai

2007

Immunobiology

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

C1 inhibitor: Biologic activities that are independent of protease inhibition

Davis

Cai

2007

Immunobiology

View full text Add to dashboard Cite

show abstract

“…Cl-Inh is the only known inhibitor in plasma of activated Clr and Cls, components of the classical pathway of complement (18), and the major inhibitor of activated Factor XII (Hageman factor) and kallikrein of the contact pathway of coagulation (19)(20)(21)(22). Inhibition of these so-called target proteinases by functional Cl-Inh comprises both proteolytic cleavage of a substrate-like peptide bond in the reactive center of the inhibitor and covalent linkage of the proteinase to the inhibitor: formation of bimolecular proteinase-C1-Inh complexes (18,20,(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Nuijens¹,

Eerenberg-Belmer²,

Huijbregts³

et al. 1989

J. Clin. Invest.

137

View full text Add to dashboard Cite

Activation of both the complement system and the contact system of intrinsic coagulation is implicated in the pathophysiology of sepsis. Because C1 inhibitor (Cl-Inh) (M, 110,000). Elevated iCl-Inh levels (_ 0.13 ,uM) were found in 81% of all patients, sometimes up to 1.6 MM. Levels of iCl-Inh on admission appeared to be of prognostic value: iCl-Inh was higher in 27 patients who died than in 21 patients who survived (P = 0.003). The mortality in 15 patients with iCl-Inh levels up to 0.2,uM was 27%, but in 12 patients with plasma iCl-Inh exceeding 0.44 gM, the mortality was 83%. The overall mortality in the patients with sepsis was 56%. We propose that the cleavage of Ci-Inh in patients with sepsis reflects processes that play a major role in the development of fatal complications during sepsis.

show abstract

“…C1-Inh is the major inhibitor of C1s and C1r of the classical pathway of complement and also an inhibitor of the contact system proteases, factor XIIa, kallikrein, and factor XIa (2)(3)(4)(5)(6)(7)(8)(9). A lack of this inhibitor may result in recurrent episodes of acute, local, circumscribed edema of the skin or mucosa.…”

mentioning

confidence: 99%

The Functional Integrity of the Serpin Domain of C1-inhibitor Depends on the Unique N-terminal Domain, as Revealed by a Pathological Mutant

Bos

Lubbers

Roem

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

C1-inhibitor (C1-InhThe autosomal dominant disease hereditary angioedema (HAE) 1 is caused by functional deficiency of C1-inhibitor (C1-Inh) (1). C1-Inh is the major inhibitor of C1s and C1r of the classical pathway of complement and also an inhibitor of the contact system proteases, factor XIIa, kallikrein, and factor XIa (2-9). A lack of this inhibitor may result in recurrent episodes of acute, local, circumscribed edema of the skin or mucosa. The most serious and potentially life-threatening manifestation of the disease is laryngeal edema (10). HAE is inherited as an autosomal dominant trait; affected individuals are heterozygous. Based on the relative levels of functional and antigenic C1-Inh, two types of HAE have traditionally been described. In type I (Ϯ 85% of HAE patients), defective expression of one allele results in low antigenic and functional levels. In type II (Ϯ15% of HAE patients), levels of functional C1-Inh are low, but C1-Inh antigen levels are normal because of the presence of a dysfunctional mutant protein. Although heterozygosity would suggest functional C1-Inh levels of around 50% in HAE, these levels are lower than 50%, typically 5-30%, which is ascribed to increased C1 activation and C1-Inh consumption (10, 11). However, the description of low levels of non-functional C1-Inh mutants in patients with type I HAE has demonstrated that the distinction between types I and II HAE is not absolute (12). For example, low levels of dysfunctional mutant protein may occur in cases where the mutation also leads to defective protein secretion (12, 13). Many different mutations can lead to dysfunctional C1-Inh, as has recently been reviewed (14). C1-Inh is a human plasma glycoprotein and a member of the serine protease inhibitor (serpin) family to which antithrombin III (ATIII), plasminogen activator inhibitor 1, and ␣1-antitrypsin also belong. Serpins are suicide inhibitors that function as a set mousetrap by forming highly stable complexes with their cognate proteases. In its active form, a serpin has a metastable structure with a flexible reactive site loop that protrudes from the core of the molecule, the central ␤-sheet. The key residues P1-P1Ј form the reactive site, a pseudosubstrate for the target protease. Upon proteolytic attack on this bond, the reactive site loop is pulled into the central ␤-sheet, inducing a dramatic conformational change that results in the formation of covalent complexes between inhibitor and protease (15, 16). Recent crystallographic studies support the idea that during complex for- 1 The abbreviations used are: HAE, hereditary angioedema; C1, complement factor 1; C1-Inh, C1 esterase inhibitor, inhibitor of C1, coagulation factors XIIa, XIa, and kallikrein; WT, wild type; C1-Inh 76 , C1-Inh 98 , and C1-Inh 115 , C1-Inh deletion mutants starting at amino acid 76, 98, and 115, respectively; ⌬3 C1-Inh, C1-Inh mutant lacking amino acids 62-116; ATIII, antithrombin III; mAB, monoclonal antibody; RII, mAb reacting with all forms of C1-Inh; Kok-12, mAb reacting with cleaved...

show abstract

Interaction of ¹²⁵I‐labelled complement subcomponents Cr and Cs with protease inhibitors in plasma

Cited by 144 publications

References 14 publications

C1 inhibitor: Biologic activities that are independent of protease inhibition

C1 inhibitor: Biologic activities that are independent of protease inhibition

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

The Functional Integrity of the Serpin Domain of C1-inhibitor Depends on the Unique N-terminal Domain, as Revealed by a Pathological Mutant

Contact Info

Product

Resources

About

Interaction of 125I‐labelled complement subcomponents Cr and Cs with protease inhibitors in plasma

Cited by 144 publications

References 14 publications

C1 inhibitor: Biologic activities that are independent of protease inhibition

C1 inhibitor: Biologic activities that are independent of protease inhibition

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

The Functional Integrity of the Serpin Domain of C1-inhibitor Depends on the Unique N-terminal Domain, as Revealed by a Pathological Mutant

Contact Info

Product

Resources

About

Interaction of ¹²⁵I‐labelled complement subcomponents Cr and Cs with protease inhibitors in plasma