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J Infect Dis. 2016 Jul 1;214(1):140-50. doi: 10.1093/infdis/jiw100. Epub 2016 Mar 14.

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.

Author information

1
Department of Immunology K. G. Jebsen IRC, University of Oslo.
2
Department of Immunology K. G. Jebsen IRC, University of Oslo Research Laboratory, Nordland Hospital Bodø Faculty of Health Sciences K. G. Jebsen TREC, University of Tromsø
3
Research Laboratory, Nordland Hospital Bodø Faculty of Health Sciences K. G. Jebsen TREC, University of Tromsø
4
Research Laboratory, Nordland Hospital Bodø
5
Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.
6
Department of Immunology Intervention Center and Clinic for Emergencies and Critical Care, Oslo University Hospital K. G. Jebsen IRC, University of Oslo.
7
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
8
Department of Immunology K. G. Jebsen IRC, University of Oslo Research Laboratory, Nordland Hospital Bodø Faculty of Health Sciences K. G. Jebsen TREC, University of Tromsø Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.

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.

KEYWORDS:

CD14; TLR; complement; eritoran; sepsis; treatment

PMID:
26977050
PMCID:
PMC4907417
DOI:
10.1093/infdis/jiw100
[Indexed for MEDLINE]
Free PMC Article

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