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Published on: March 1, 2011
Combined Inhibition of Complement and CD14 Attenuates Bacteria-Induced Inflammation in Human Whole Blood More
Alice Gustavsen1, Stig Nymo2, Anne Landsem3
1Department of Immunology K. G. Jebsen IRC, University of Oslo.
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.
Insights
Inhibiting Toll-like receptor 4 (TLR4) alone failed to treat sepsis. CD14 inhibition, especially combined with complement inhibition, proved more effective than TLR4-MD2 inhibition for bacterial sepsis treatment.
Area of Science:
- Immunology
- Sepsis Pathophysiology
- Complement System
Background:
- Single inhibition of Toll-like receptor 4 (TLR4)-MD2 complex was ineffective for sepsis treatment.
- CD14 acts as a coreceptor for TLRs, including TLR4 and TLR2.
- Investigating CD14 inhibition's role in modulating inflammatory responses is crucial.
Purpose of the Study:
- To compare the efficacy of CD14 inhibition versus TLR4-MD2 inhibition (eritoran) in sepsis.
- To evaluate the combined effect of CD14 inhibition and complement inhibition (compstatin) on bacterial sepsis.
- To analyze the impact on bacteria-induced inflammatory responses in human whole blood.
Main Methods:
- Measurement of cytokines using multiplex technology.
- Quantification of leukocyte activation markers (CD11b, CD35) via flow cytometry.
- Inhibition assays using eritoran, anti-CD14, and compstatin (Cp40) against bacterial stimuli.
Main Results:
- Both anti-CD14 and eritoran inhibited lipopolysaccharide (LPS)-induced inflammatory markers.
- Anti-CD14 demonstrated superior inhibition of LPS-binding and monocyte activation compared to eritoran.
- Combined Cp40 and anti-CD14 significantly outperformed other combinations in reducing inflammatory markers against E. coli and S. aureus.
Conclusions:
- Anti-CD14 is more effective than eritoran in inhibiting whole bacteria-induced inflammation.
- Combining CD14 inhibition with complement inhibition offers a potent strategy for treating bacterial sepsis.
- This combined approach shows promise for future sepsis therapeutic development.
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