title: Combined inhibition of complement and CD14 efficiently attenuated the inflammatory response induced by Staphylococcus aureus in a human whole blood model.
abstract: The complement and TLR systems are activated in sepsis, contributing to an unfavorable inflammatory "storm." Combined inhibition of these systems has been documented to efficiently attenuate the inflammatory responses induced by Gram-negative bacteria. In this study, we hypothesized that the combined inhibition would attenuate the inflammatory responses induced by Gram-positive bacteria. Staphylococcus aureus bacteria (strains Cowan and Wood), as well as S. aureus cell wall lipoteichoic acid (LTA), were incubated in thrombin-inhibited human whole blood. Complement was inhibited at the level of C3 and C5, and the TLRs by inhibiting CD14 and TLR2. Thirty-four inflammatory markers were measured by multiplex technology and flow cytometry. Thirteen markers increased significantly in response to Cowan and Wood, and 12 in response to LTA. Combined inhibition with the C3 inhibitor compstatin and the anti-CD14 Ab 18D11 significantly reduced 92 (Cowan, LTA) and 85% (Wood) of these markers. Compstatin alone significantly reduced 54 (Cowan), 38 (Wood), and 83% (LTA), whereas anti-CD14 alone significantly reduced 23, 15, and 67%, respectively. Further experiments showed that the effects of complement inhibition were mainly due to inhibition of C5a interaction with the C5a receptor. The effects on inhibiting CD14 and TLR2 were similar. The combined regimen was more efficient toward the bacterial effects than either complement or anti-CD14 inhibition alone. Complement was responsible for activation of and phagocytosis by both granulocytes and monocytes. Disrupting upstream recognition by inhibiting complement and CD14 efficiently attenuated S. aureus-induced inflammation and might be a promising treatment in both Gram-negative and Gram-positive sepsis.
authors: Research Laboratory, Nordland Hospital, Bodø 8092, Norway;
authors: Espen W
authors: EW
authors: Skjeflo
authors: Dorte
authors: D
authors: Christiansen
authors: Terje
authors: T
authors: Espevik
authors: Erik W
authors: EW
authors: Nielsen
authors: Tom E
authors: TE
authors: Mollnes
mesh_terms: D003176:Complement C3 / Q000276:immunology; D003182:Complement C5 / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use; D007249:Inflammation / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D010456:Peptides, Cyclic / Q000276:immunology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D044087:Receptor, Anaphylatoxin C5a / Q000276:immunology; D013203:Staphylococcal Infections / Q000150:complications / Q000276:immunology* / Q000517:prevention & control; D013211:Staphylococcus aureus / Q000187:drug effects / Q000276:immunology*; D013682:Teichoic Acids / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000276:immunology; D016896:Treatment Outcome
chemical_list: C488033:C5AR1 protein, human; D003176:Complement C3; D003182:Complement C5; D016207:Cytokines; D007140:Immunoglobulin Fab Fragments; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; C495342:TLR2 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; C111828:compstatin; C009900:lipoteichoic acid; D003165:Complement System Proteins