Anti-inflammatory effects of C1-Inhibitor in porcine and human whole blood are independent of its protease inhibition activity.
C1-Inhibitor (C1-INH) is an important biological inhibitor, regulating several protein cascade systems. Recent research has shown that the molecule exhibits properties not dependent on its protease inhibition activity. Serum and whole blood from pigs and humans were pre-incubated with C1-INH, iC1-INH or the complement inhibitors SPICE or compstatin. Whole, live Escherichia coli were then added for further incubation. Complement activation, a range of cytokines, chemokines and growth factors, as well as the leukocyte activation markers wCD11R3 (pig) and CD11b (human) were measured. Both C1-INH and iC1-INH dose-dependently and significantly (P<0.05) reduced a range of E. coli-induced pro-inflammatory cytokines and chemokines in porcine and human whole blood, as well as growth factors in human whole blood. Differences between the two forms of C1-INH and between the two species were modest. Most of these anti-inflammatory effects could not be explained by complement inhibition, as specific complement inhibitors had minor effect on several of the mediators. C1-Inhibitor had no inhibitory effect on E. coli-induced complement activation, while iC1-INH enhanced complement activation. The presented data indicate that C1-INH has broad anti-inflammatory effects in E. coli-induced inflammation in pig and human whole blood. These effects are largely independent of the protease inhibition activity.
Thorgersen
Ebbe Billmann
EB
Institute of Immunology, Rikshospitalet University Hospital, and University of Oslo, Oslo, Norway. ebbtho@rr-research.no
Ludviksen
Judith K
JK
Lambris
John D
JD
Sfyroera
Georgia
G
Nielsen
Erik Waage
EW
Mollnes
Tom Eirik
TE
D000818:Animals; D000893:Anti-Inflammatory Agents; D000925:Anticoagulants / Q000494:pharmacology; D018845:CD11 Antigens / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D003167:Complement Activation / Q000187:drug effects; D003174:Complement C1 Inactivator Proteins / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D016905:Gram-Negative Bacterial Infections / Q000473:pathology; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007249:Inflammation / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008262:Macrophage Activation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D018845:CD11 Antigens; D018925:Chemokines; D003174:Complement C1 Inactivator Proteins; D016207:Cytokines; D006629:Hirudins; D007202:Indicators and Reagents; D036341:Intercellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D011994:Recombinant Proteins; C083544:lepirudin