Combined inhibition of complement and CD14 abolish E. coli-induced cytokine-, chemokine- and growth factor-synthesis in human whole blood

Brekke, Ole-Lars; Christiansen, Dorte; Fure, Hilde; Pharo, Anne; Fung, Michael; Riesenfeld, Johan; Mollnes, Tom Eirik

doi:10.1016/j.molimm.2008.05.017

Cited by 53 publications

(55 citation statements)

References 39 publications

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“…Yet, the use of anti-CD14 exerted very little effect on its own. The effect of combined CD14 and complement inhibition is in line with our previous studies with Gram-negative bacteria (14,20), although the contribution of complement when compared with CD14 seems to be substantially greater in the response to Gram-positive bacteria than in response to Gram-negative. Thus, identifying complement and CD14 as main triggers of inflammation in response to both Gram-negative and Gram-positive bacteria also make them eligible for a double blockade.…”

Section: Discussionsupporting

confidence: 89%

“…We have previously shown that combined inhibition of C3 and CD14 is a powerful tool to attenuate the inflammatory responses (cytokine release, oxidative burst, phagocytosis, and expression of adhesion molecules and tissue factor) induced by Gram-negative bacteria (Escherichia coli and Neisseria meningitidis), which are mainly triggered through TLR4 stimulation (20). CD14 is a known coreceptor with several of the TLRs, including TLR4 and TLR2 (21).…”

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confidence: 99%

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Combined Inhibition of Complement and CD14 Efficiently Attenuated the Inflammatory Response Induced byStaphylococcus aureusin a Human Whole Blood Model

Skjeflo

Christiansen

Espevik

et al. 2014

The Journal of Immunology

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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.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Combined Inhibition of Complement and CD14 Efficiently Attenuated the Inflammatory Response Induced byStaphylococcus aureusin a Human Whole Blood Model

Skjeflo

Christiansen

Espevik

et al. 2014

The Journal of Immunology

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“…In a previous study, we also found a "delicate balance" between the complement activation and cytokine secretion wherein high complement activation seemed to be accompanied by low cytokine secretion and vice versa (23). The interplay between complement activation and cytokine secretion is complex, with some cytokines being complement dependent whereas others are complement independent (36,37). Cytokines may, however, indirectly contribute to complement activation, e.g., by increasing the expression of anaphylatoxin receptors (38).…”

Section: Articlesmentioning

confidence: 84%

Staphylococcus epidermidis biofilms induce lower complement activation in neonates as compared with adults

et al. 2012

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Background: Staphylococcus epidermidis (se) is an important cause of late-onset sepsis in neonates. se frequently produces a polysaccharide intercellular adhesin (PIa) biofilm, important in the pathogenesis of these infections. Little is known about how the neonatal innate immune system reacts to se biofilm-associated infections. Our hypothesis was that se biofilms induce a lower complement activation in neonates as compared with adults. Methods: cord blood from term infants (n = 15) and blood from adults (n = 6) were studied in an ex vivo whole-blood sepsis model. a PIa biofilm-producing strain (se1457) and its isogenic mutant (M10), producing a non-PIa biofilm, were used. results: Both se biofilms induced stronger complement activation in adult than in cord blood (P ≤ 0.033). We found lower levels of antibodies toward both PIa (P = 0.002) and the whole bacterium (P = 0.001) in cord vs. adult blood. By contrast, the interleukin-8 (IL-8) and IL-6 secretion were higher in cord than in adult blood (P ≤ 0.002). The PIa biofilm induced stronger complement activation than the non-PIa biofilm. conclusion: We conclude that the neonatal complement system exhibits a maturational deficiency. This may reduce the ability of neonates to combat biofilm-associated se infections. Staphylococcus epidermidis (SE) is the most prevalent pathogen causing late-onset sepsis in neonates (1). These infections are seldom lethal, but they cause significant morbidity, especially in preterm infants (1,2). SE infections are often associated with biofilm production on the surface of foreignbody implants (3,4). Biofilms are adherent multicellular bacterial aggregates embedded in a self-produced extracellular matrix. The best-described matrix compound in SE biofilms is a β-(1,6)-linked N-acetylglucosamine named polysaccharide intercellular adhesin (PIA) (5,6).SE and SE biofilms interfere with the host immune response at different levels. PIA biofilms inhibit the action of antimicrobial peptides (7), decrease neonatal inflammatory response (8), and decrease phagocytosis and degranulation by neutrophils (7). Biofilms may "decoy" antibodies and complement on the bacterial surface and thereby decrease opsonization and phagocytosis (9-11). The ability of biofilm-producing bacteria to avoid immune clearance and the general immaturity of the neonatal immune system (12) are postulated to increase the risk of neonatal SE sepsis (13). As compared with adults, neonates have a lower quantitative and qualitative complement activation (14,15), reduced upregulation of cellular response (12), and an immature cytokine response pattern (16)(17)(18)(19). Preterm infants demonstrate a markedly reduced capacity to upregulate oxidative burst in leukocytes in response to SE (20). However, some authors have reported that SE may induce a similar proinflammatory cytokine response in neonates and adults (19,21), indicating a differential maturation of various parts of the neonatal innate immune system. Differences in maturation have also been described when challenging t...

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“…If so, tissue targeting of anti-CD14 could be a treatment approach. As complement inhibitors and anti-CD14 were shown to have complementary and differential inhibitory effects in vitro in pigs, and as a pronounced inhibitory synergism is previously shown in vitro in humans (64,139,171), it would be extremely interesting to investigate a combination of a complement inhibitor and anti-CD14 or CyP, in vivo in our pig model. Unfortunately, an available large scale produced specific complement inhibitor working in pigs has been impossible to provide up till now.…”

Section: Future Perspectivesmentioning

confidence: 86%

Candidate inhibitors of porcine complement

Thorgersen¹,

Ghebremariam²,

Thurman³

et al. 2007

Molecular Immunology

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Combined inhibition of complement and CD14 abolish E. coli-induced cytokine-, chemokine- and growth factor-synthesis in human whole blood

Cited by 53 publications

References 39 publications

Combined Inhibition of Complement and CD14 Efficiently Attenuated the Inflammatory Response Induced byStaphylococcus aureusin a Human Whole Blood Model

Combined Inhibition of Complement and CD14 Efficiently Attenuated the Inflammatory Response Induced byStaphylococcus aureusin a Human Whole Blood Model

Staphylococcus epidermidis biofilms induce lower complement activation in neonates as compared with adults

Candidate inhibitors of porcine complement

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