Inhibition of Complement and CD14 Attenuates theEscherichia coli-Induced Inflammatory Response in Porcine Whole Blood
Autor: | Georgia Sfyroera, Peter Gaustad, Anne Pharo, Ebbe Billmann Thorgersen, Tom Eirik Mollnes, Girish J. Kotwal, Karin Haverson, Anne K. Axelsen |
---|---|
Rok vydání: | 2009 |
Předmět: |
Lipopolysaccharides
Swine Immunology Lipopolysaccharide Receptors Inflammation Microbiology Proinflammatory cytokine Viral Matrix Proteins Escherichia coli medicine Animals Host Response and Inflammation Innate immune system biology CD11 Antigens Antibodies Monoclonal Complement System Proteins Immunity Innate Complement system Infectious Diseases Gene Expression Regulation Factor H biology.protein TLR4 Cytokines Parasitology medicine.symptom Complement component 5a Granulocytes Complement control protein |
Zdroj: | Infection and Immunity. 77:725-732 |
ISSN: | 1098-5522 0019-9567 |
Popis: | The innate immune response is a double-edged sword in systemic inflammation and sepsis. Uncontrolled or inappropriate activation can damage and be lethal to the host. Several studies have investigated inhibition of downstream mediators, including tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Emerging evidence indicates that upstream inhibition is a better therapeutic approach for attenuating damaging immune activation. Therefore, we investigated inhibition of two central innate immune pathways, those of complement and CD14/Toll-like receptor 4 (TLR4)/myeloid differentiation protein 2 (MD-2), in a porcine in vitro model ofEscherichia coli-induced inflammation. Porcine whole blood anticoagulated with lepuridin, which did not interfere with the complement system, was incubated withE. colilipopolysaccharide (LPS) or whole bacteria. Inhibitors of complement and CD14 and thus the LPS CD14/TLR4/MD-2 receptor complex were tested to investigate the effect on the inflammatory response. A broad range of inflammatory readouts were used to monitor the effect. Anti-CD14 was found to saturate the CD14 molecule on granulocytes and completely inhibited LPS-induced proinflammatory cytokines in a dose-dependent manner. Anti-CD14 significantly reduced the levels of theE. coli-induced proinflammatory cytokines TNF-α and IL-1β, but not IL-8, in a dose-dependent manner. No effect on bacterial clearance was seen. Vaccinia complement control protein and smallpox inhibitor of complement enzymes, twoOrthopoxvirus-encoded complement inhibitors, completely inhibited complement activation. Furthermore, these agents almost completely inhibited the expression of wCD11R3, which is associated with CD18 as a β2 integrin, on porcine granulocytes and decreased IL-8 levels significantly in a dose-dependent manner. As expected, complement inhibition reduced bacterial clearance. We conclude that inhibition of complement and CD14 attenuatesE. coli-induced inflammation and might be used as a therapeutic regimen in gram-negative sepsis along with appropriate treatment with antibiotics. |
Databáze: | OpenAIRE |
Externí odkaz: |