%0 Journal Article %1 Gustavsen:2016cxa %A Gustavsen, Alice %A Nymo, Stig %A Landsem, Anne %A Christiansen, Dorte %A Ryan, Liv %A Husebye, Harald %A Lau, Corinna %A Pischke, Søren E %A Lambris, John D. %A Espevik, Terje %A Mollnes, Tom E. %D 2016 %J J.Infect.Dis. %K imported %N 1 %P 140--150 %R 10.1093/infdis/jiw100 %T Combined Inhibition of Complement and CD14 Attenuates Bacteria-Induced Inflammation in Human Whole Blood More Efficiently Than Antagonizing the Toll-like Receptor 4-MD2 Complex. %U https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiw100 %V 214 %X BACKGROUND:Single inhibition of the Toll-like receptor 4 (TLR4)-MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood. METHODS:Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry. RESULTS:Lipopolysaccharide (LPS)-induced inflammatory markers were efficiently abolished by both anti-CD14 and eritoran. Anti-CD14 was significantly more effective than eritoran in inhibiting LPS-binding to HEK-293E cells transfected with CD14 and Escherichia coli-induced upregulation of monocyte activation markers (P < .01). Combining Cp40 with anti-CD14 was significantly more effective than combining Cp40 with eritoran in reducing E. coli-induced interleukin 6 (P < .05) and monocyte activation markers induced by both E. coli (P < .001) and Staphylococcus aureus (P < .01). Combining CP40 with anti-CD14 was more efficient than eritoran alone for 18 of 20 bacteria-induced inflammatory responses (mean P < .0001). CONCLUSIONS:Whole bacteria-induced inflammation was inhibited more efficiently by anti-CD14 than by eritoran, particularly when combined with complement inhibition. Combined CD14 and complement inhibition may prove a promising treatment strategy for bacterial sepsis.

@article{Gustavsen:2016cxa, abstract = {BACKGROUND:Single inhibition of the Toll-like receptor 4 (TLR4)-MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood. METHODS:Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry. RESULTS:Lipopolysaccharide (LPS)-induced inflammatory markers were efficiently abolished by both anti-CD14 and eritoran. Anti-CD14 was significantly more effective than eritoran in inhibiting LPS-binding to HEK-293E cells transfected with CD14 and Escherichia coli-induced upregulation of monocyte activation markers (P < .01). Combining Cp40 with anti-CD14 was significantly more effective than combining Cp40 with eritoran in reducing E. coli-induced interleukin 6 (P < .05) and monocyte activation markers induced by both E. coli (P < .001) and Staphylococcus aureus (P < .01). Combining CP40 with anti-CD14 was more efficient than eritoran alone for 18 of 20 bacteria-induced inflammatory responses (mean P < .0001). CONCLUSIONS:Whole bacteria-induced inflammation was inhibited more efficiently by anti-CD14 than by eritoran, particularly when combined with complement inhibition. Combined CD14 and complement inhibition may prove a promising treatment strategy for bacterial sepsis.}, added-at = {2017-12-08T05:18:19.000+0100}, affiliation = {Department of Immunology K. G. Jebsen IRC, University of Oslo.}, author = {Gustavsen, Alice and Nymo, Stig and Landsem, Anne and Christiansen, Dorte and Ryan, Liv and Husebye, Harald and Lau, Corinna and Pischke, S{\o}ren E and Lambris, John D. and Espevik, Terje and Mollnes, Tom E.}, biburl = {https://www.bibsonomy.org/bibtex/2dd0fb6421e58e3bf1508c2d21fa4e27c/lambris}, date-added = {2017-12-08T04:15:43GMT}, date-modified = {2017-12-08T04:17:37GMT}, doi = {10.1093/infdis/jiw100}, interhash = {b6e13eb32b97ad1d8cc9f68aa7246922}, intrahash = {dd0fb6421e58e3bf1508c2d21fa4e27c}, journal = {J.Infect.Dis.}, keywords = {imported}, language = {English}, month = jul, number = 1, pages = {140--150}, pmcid = {PMC4907417}, pmid = {26977050}, rating = {0}, timestamp = {2017-12-08T05:18:19.000+0100}, title = {{Combined Inhibition of Complement and CD14 Attenuates Bacteria-Induced Inflammation in Human Whole Blood More Efficiently Than Antagonizing the Toll-like Receptor 4-MD2 Complex.}}, uri = {\url{papers3://publication/doi/10.1093/infdis/jiw100}}, url = {https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiw100}, volume = 214, year = 2016 }