CD14 Plays No Major Role in Shock Induced by Staphylococcus aureus but Down-Regulates TNF-a Production (original) (raw)
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The Journal of Immunology, 1999
Recent in vitro studies have suggested that CD14, a major receptor for LPS, may also be a receptor for cell wall components of Gram-positive bacteria and thus play a role in Gram-positive shock. To analyze the in vivo role of CD14 in responses to Grampositive bacteria, CD14-deficient and control mice were injected with Staphylococcus aureus, and the effects on lethality, bacterial clearance, and production of cytokines were analyzed. Survival of CD14-deficient and control mice did not differ significantly after administration of various doses of either unencapsulated or encapsulated S. aureus; furthermore, mice in both groups displayed similar symptoms of shock. In addition, inflammatory cytokines such as TNF-␣ and IL-6 were readily detectable in the serum of CD14-deficient mice injected with live or antibiotic-killed S. aureus. Surprisingly, the serum concentration of TNF-␣ in CD14deficient mice was at least threefold higher than in control mice after injection of either unencapsulated or encapsulated S. aureus, suggesting that CD14 down-regulates TNF-␣. A similar increase in serum TNF-␣ occurred when CD14-deficient animals were injected with gentamicin-killed bacteria even though no symptoms of shock were observed. These studies indicate that CD14, in contrast to its key function in responses to the Gram-negative bacterium, Escherichia coli 0111, does not play a prominent role in septic shock induced by S. aureus, and that the symptoms of S. aureus shock are not due solely to TNF-␣.
The Journal of Immunology
Recent in vitro studies have suggested that CD14, a major receptor for LPS, may also be a receptor for cell wall components of Gram-positive bacteria and thus play a role in Gram-positive shock. To analyze the in vivo role of CD14 in responses to Gram-positive bacteria, CD14-deficient and control mice were injected with Staphylococcus aureus, and the effects on lethality, bacterial clearance, and production of cytokines were analyzed. Survival of CD14-deficient and control mice did not differ significantly after administration of various doses of either unencapsulated or encapsulated S. aureus; furthermore, mice in both groups displayed similar symptoms of shock. In addition, inflammatory cytokines such as TNF-alpha and IL-6 were readily detectable in the serum of CD14-deficient mice injected with live or antibiotic-killed S. aureus. Surprisingly, the serum concentration of TNF-alpha in CD14-deficient mice was at least threefold higher than in control mice after injection of either ...
Antibodies against CD14 protect primates from endotoxin-induced shock
Journal of Clinical Investigation, 1996
Lipopolysaccharide (LPS), residing in the outer membrane of all gram-negative bacteria, is considered a major initiating factor of the gram-negative septic shock syndrome in humans. LPS forms a complex with the LPS binding protein (LBP) in plasma, and LPS-LBP complexes engage a specific receptor, CD14, on the surface of myeloid cells, leading to the production of potent proinflammatory cytokines. The major goal of this study was to test the importance of the CD14 pathway in vivo in a primate model that is similar to human septic shock. Primates were pretreated with one of two different inhibitory anti-CD14 mAbs, then challenged with intravenous endotoxin (375 g/kg/h) for 8 h. The anti-CD14 treatment regimens were successful in preventing profound hypotension, reducing plasma cytokine levels (TNF-␣ , IL-1  , IL-6, and IL-8), and inhibiting the alteration in lung epithelial permeability that occurred in animals treated with LPS and an isotype-matched control antibody. These results demonstrate for the first time the importance of the CD14 pathway in a primate model that is similar to human septic shock. Inhibition of the CD14 pathway represents a novel therapeutic approach to treating this life-threatening condition.
Systemic CD14 Inhibition Attenuates Organ Inflammation in Porcine Escherichia coli Sepsis
Infection and Immunity, 2013
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Journal of Thrombosis and Haemostasis, 2020
Gram-negative bacterial sepsis induces robust inflammation primarily via LPS signaling through TLR4, a process that involves the GPI-anchored co-receptor CD14 transferring LPS to the TLR4/MD-2 complex. Our group has shown that systemic inhibition of CD14 attenuates organ inflammation in a porcine model of E. coli sepsis. Here we investigated the effect of anti-CD14 antibody on thrombo-inflammation, including complement activation and hemostasis, as well as cell death/organ injury and mortality in a baboon model of lethal E. coli sepsis. Two experimental groups of 5 animals each were studied: (i) E. coli challenge; (ii) E. coli challenge plus anti-CD14 administered intravenously 30 minutes before E. coli. As compared to the control group, anti-CD14 reduced to different extents plasma cytokines (TNF, IFN-γ, MCP-1, IL-1β, IL-8, IL-1RA) and prevented the robust complement activation induced by E. coli, as shown by C3b, C5a and C5b-9. The coagulation, fibrinolysis, cell death and organ function biomarkers were changed at varying levels. Most prominent was the strong decrease of PAI-1, accompanied by enhanced fibrinolysis in the anti-CD14 group. The treatment improved bacteria clearance, whereas LPS levels were similar in both groups. Importantly, 2 animals passed the 7-day end-point criteria (survivor), while 3 animals had prolonged survival compared to non-treated controls. Parameters that showed significant differences between survivors and non-survivors in the anti-CD14 group include leukocyte number, TAFI, HMGB1, creatinine and some cytokines. Our results highlight the crosstalk between Toll-like receptors, hemostasis and complement, and suggest a protective role of anti-CD14 treatment in sepsis.
TLR4/MD-2 Monoclonal Antibody Therapy Affords Protection in Experimental Models of Septic Shock
The Journal of Immunology, 2007
Overactivation of the immune system upon acute bacterial infection leads to septic shock. Specific bacterial products potently stimulate immune cells via toll-like receptors (TLRs). Gram-negative bacteria induce a predominantly TLR4-driven signal through LPS release. To neutralize LPS signaling in experimental models of sepsis, we generated mAbs toward the TLR4/myeloid differentiation protein-2 (MD-2) complex. The binding properties of an array of selected rat mAbs differed in respect to their specificity for TLR4/MD-2 complex. The specificity of one such mAb, 5E3, to murine TLR4 was confirmed by its recognition of an epitope within the second quarter of the ectodomain. 5E3 inhibited LPS-dependent cell activation in vitro and prevented proinflammatory cytokine production in vivo following LPS challenge in a dose-dependent manner. Furthermore, 5E3 protected mice from lethal shock-like syndrome when applied using both preventative and therapeutic protocols. Most notably, in the colon ascendens stent peritonitis model of polymicrobial abdominal sepsis, administration of a single dose of 5E3 (50 g) protected mice against mortality. These results demonstrate that neutralizing TLR4/MD-2 is highly efficacious in protecting against bacterial infection-induced toxemia and offers TLR4/MD-2 mAb treatment as a potential therapy for numerous clinical indications. The Journal of Immunology, 2007, 179: 6107-6114.
Infection and Immunity, 2001
We investigated the immunopathophysiologic responses during sepsis induced by cecal ligation and puncture (CLP) in CD4-deficient (CD14 knockout [CD14KO]) mice. Our studies were designed to specifically test the role of CD14 in the inflammatory response to sepsis and to ascertain if alterations would improve morbidity or mortality. Sepsis was induced using the CLP model with appropriate antibiotic treatment. The severity of sepsis increased in the CD14KO mice with increasing puncture size (18 gauge [18G], 21G, and 25G). Following CLP, body temperature (at 12 h) and gross motor activity levels of the sham and 25G CLP groups recovered to normal, while the 21G and 18G CLP groups exhibited severe hypothermia coupled with decreased gross motor activity and body weight. There were no significant differences in survival, temperature, body weight, or activity levels between CD14KO and control mice after 21G CLP. However, CD14KO mice expressed two-to fourfold less pro-