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PMID: 20870944 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Molecular intercommunication between the complement and coagulation systems.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 185 ·No. 9 ·2010-11-01 ·Pages 5628-36

Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B, Brückner UB, Nilsson B, Gebhard F, Lambris JD, Huber-Lang M

Abstract

The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin-antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system.

MeSH Terms
Adult Aged Anaphylatoxins/metabolism Blood Coagulation/physiology Blotting, Western Chemotaxis, Leukocyte/immunology Complement Activation/physiology Complement System Proteins/metabolism Enzyme-Linked Immunosorbent Assay Female Humans Male Mast Cells/immunology,metabolism Middle Aged Neutrophils/immunology,metabolism Serine Proteases/metabolism Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Young Adult
Chemicals
Anaphylatoxins Complement System Proteins Serine Proteases
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Amara Umme
Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany.
Flierl Michael A
Rittirsch Daniel
Klos Andreas
Chen Hui
Acker Barbara
Brückner Uwe B
Nilsson Bo
Gebhard Florian
Lambris John D
Huber-Lang Markus
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0903678
Published
2010-11-01
Epub
2010-00-24
Pages
5628-36
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC3123139
Subset
IM
Grants
NIGMS NIH HHS · R01 GM062134-08 · United States
NIAID NIH HHS · P01 AI068730-04 · United States
NIAID NIH HHS · AI068730 · United States
NIAID NIH HHS · AI30040 · United States
NIAID NIH HHS · N01AI30040 · United States
NIGMS NIH HHS · GM062134 · United States
NIAID NIH HHS · R01 AI030040 · United States
NIGMS NIH HHS · R01 GM062134 · United States
NIAID NIH HHS · P01 AI068730 · United States
NIAID NIH HHS · R01 AI030040-15 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.0903678 PMC Full Text View journal details
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