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Using the cleaving bar and turning knob, cleave slowly and controllably perpendicular to the primary sample axis, from the indentation. Similarly, kallikrein-generated convertases yielded C3a Fig. To find out whether factor H also regulates kallikrein-generated convertases, we incubated C3 and factor B with kallikrein to generate C3 convertases. Factor H was added to these C3 convertases at increasing concentrations and factor B binding was assayed using factor B antiserum. This effect was dose dependent.
Similarly, factor H dissociated the alternative pathway C3 convertase generated by factor D Fig. In contrast, addition of plasmin did not form convertases. Kallikrein-generated C3b was also incubated with factor H and factor I, and degradation of C3b was detected by Western blotting. Similar C3b cleavage products 86, 46, and 43 kDa were generated by kallikrein and C3 convertases. Taken together, these data suggest that factor H decays kallikrein-generated C3 convertases and acts as a cofactor for factor I during the degradation of kallikrein-generated C3b.
One representative experiment out of 3 is shown. Plasmin fails to create convertases. IC3b generation from C3 convertase-formed C3b is shown in lane 8. A representative Western blot of 3 independent experiments is shown. The contact system is spontaneously activated upon recognition by and attachment of factor XII FXII to negatively charged surfaces [ 26 , 27 ].
To examine whether C. Liver sections were stained with antibodies specific for FXII and the fungal surface protein Pra1 pH-regulated protein 1. Binding of FXII was assessed by laser scanning microscopy. FXII was detected on the surface of C. Also, C3b deposited onto C. Thus, the contact system is activated on C. As shown here, factor H regulates the kallikrein-generated convertases. Both here and previously, we demonstrated in vitro recruitment of factor H to C. To find out whether C.
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Factor H was present on C. The addition of kallikrein enhances C3b deposition. Green, erythrocytes; red, fungal protein Pra1; blue, mouse factor H. Bacterial and fungal surfaces are immediately recognized by the host complement and contact systems. Once activated, both systems trigger a coordinated immune response that comprises opsonization, phagocytosis, acute and chronic inflammation, vascular permeability, pain, and fever [ 1 , 2 , 5 , 7 ]. Here, we have shown that kallikrein generated from prekallikrein by the induced contact system activates the complement system by cleaving C3 and factor B, with subsequent formation of an active complement C3 convertase.
Damage to host cells caused by this convertase is regulated by factor H, which decays kallikrein-generated C3 convertase and assists factor I-mediated degradation of C3b. The human pathogenic fungus, C albicans , activates both the complement and contact systems in human serum.
C3 degradation products on C. Kallikrein cleaves plasma C3 at the amide bond between R and S to generate active C3b and C3a. The cleavage site in C3 is identical to that recognized by the C3 convertase.
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In contrast to plasmin, kallikrein cleaves C3 exclusively at this position and no further cleavage products appear. Mature human prekallikrein, a precursor of plasma kallikrein, comprises amino acids [ 28 ] and activation of prekallikrein to kallikrein is induced by cleavage at the amide bond between R and I , resulting in production of a heterodimer comprising an N-terminal heavy chain and a C-terminal light chain containing a C -C bond [ 28 ].
The light chain includes a serine protease domain harboring a triad of catalytic residues. The main substrate of kallikrein is kininogen, and cleavage of the latter generates kallidin lysil-bradykinin , which induces vascular permeability and promotes nitric oxide and prostaglandin release by endothelial cells, resulting in vasodilation [ 29 , 30 , 31 ].
Kallikrein also cleaves factor B; the cleavage patterns of kallikrein and factor D are indistinguishable. These results confirm previous observations by DiScipio [ 14 ], who demonstrated magnesium ion-dependent cleavage of factor B by kallikrein. Thus, kallikrein induces the C3 convertase amplification loop in the absence of factor D, and links the contact activation and complement systems to enhance opsonization, vascular permeability, and recruitment of inflammatory cells to generate a local immune response.
Kallikrein can also activate the classical complement pathway [ 32 ]. Activation of both of these systems contact and complement causes signs and symptoms often seen in those with septic shock and hereditary angioedema. Hereditary angioedema is a condition caused by a deficiency or defect in the C1 inhibitor [ 33 , 34 ]. Similar to kallikrein, FXII can activate C1 of the classical pathway [ 35 ] and factor B of the alternative pathway [ 14 ].
Upon contact with NHS, C. Factor XII then binds strongly to the fungal surface and activates kallikrein and kinins. A recent study suggests that kinins released at the C.
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Similarly, C. However, kallikrein cleaves HMWK to yield bradykinin, which is an important proinflammatory mediator that recruits immune cells such as neutrophils to the sites inhabited by the infectious microbe. As shown herein, kallikrein also activates complement to boost the immune response. Since kallikrein also cleaves complement component C5, it also activates the terminal complement pathway [ 12 ].
Low thrombin C3 cleavage activity was previously also described by Foley et al. Kallikrein-generated C3 convertases are inactivated by complement factor H. Factor H binds to stressed human cell surfaces and blocks the complement cascade. In the presence of low levels of factor H as in patients harboring mutated or dysfunctional protein , the endothelium is less well protected, resulting in diseases such as hemolytic uremic syndrome [ 8 ]. Bound factor H then dissociates the C3 convertases generated by complement and kallikrein. Here, we also showed that plasmin in contrast to kallikrein inactivates C3 convertases.
Taken together, these data suggest that C. Previous reports show that the contact system is activated by bacterial cell walls [ 40 ]. Similar to C. However, these pathogens also recruit and exploit factor H [ 41 ]. The full relevance of kallikrein-mediated complement activation to host defense in vivo remains unclear; however, some individuals with a severe deficiency of contact factors are highly susceptible to bacterial infections [ 14 ]. Our findings support a role of kallikrein in the defense response to infections.
Similarly, overactivation of the contact system is expected to also activate the complement system. Furthermore, complement activation via kallikrein may need to be considered in respect to therapeutic complement inhibition. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
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