Phospholipids Inhibit Lipopolysaccharide (LPS)-Induced Cell Activation: A Role for LPS-Binding Protein

Mueller, Mareike; Brandenburg, Klaus; Dedrick, Russ; Schromm, Andra B.; Seydel, Ulrich

doi:10.4049/jimmunol.174.2.1091

Cited by 65 publications

(73 citation statements)

References 39 publications

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“…These results could be explained by the formation of LTA⅐LBP complexes leading to inactivation of LTA and LBP functions. A similar mechanism has been suggested for the neutralization of sLBP by phospholipids (39). Interaction of LTA with serum proteins has been reported previously, but the data published on the requirement of soluble LBP are conflicting.…”

Section: Discussionmentioning

confidence: 78%

“…Cytokine Determination-Human TNF␣ and human IL-6 were determined in pooled cell-free supernatants of stimulated cells by sandwich enzyme-linked immunosorbent assay using monoclonal mouse antibody against human IL-6 and PODconjugated rabbit anti-human IL-6 antibody and monoclonal mouse antibody against human TNF␣ and POD-conjugated rabbit anti-human TNF␣ antibody, respectively (Intex, Muttant, Switzerland) as stated in detail elsewhere (39). Rat TNF␣ and human IL-8 were determined in pooled cell-free supernatants of stimulated cells by sandwich enzyme-linked immunosorbent assay using Cytosets from BIOSOURCE (Solingen, Germany) exactly according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

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Cell Activation of Human Macrophages by Lipoteichoic Acid Is Strongly Attenuated by Lipopolysaccharide-binding Protein

et al. 2006

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Lipoteichoic acid (LTA) represents immunostimulatory molecules expressed by Gram-positive bacteria. They activate the innate immune system via Toll-like receptors. We have investigated the role of serum proteins in activation of human macrophages by LTA from Staphylococcus aureus and found it to be strongly attenuated by serum. In contrast, the same cells showed a sensitive response to LTA and a significantly enhanced production of tumor necrosis factor ␣ under serum-free conditions. We show that LTA interacts with the serum protein lipopolysaccharide-binding protein (LBP) and inhibits the integration of LBP into phospholipid membranes, indicating the formation of complexes of LTA and soluble LBP. The addition of recombinant human LBP to serum-free medium inhibited the production of tumor necrosis factor ␣ and interleukins 6 and 8 after stimulation of human macrophages with LTA in a dose-dependent manner. Using anti-LBP antibodies, this inhibitory effect could be attributed to soluble LBP, whereas LBP in its recently described transmembrane configuration did not modulate cell activation. Also, using primary alveolar macrophages from rats, we show a sensitive cytokine response to LTA under serum-free culture conditions that was strongly attenuated in the presence of serum. In summary, our data suggest that innate immune recognition of LTA is organ-specific with negative regulation by LBP in serum-containing compartments and sensitive recognition in serum-free compartments like the lung.

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Section: Discussionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Cell Activation of Human Macrophages by Lipoteichoic Acid Is Strongly Attenuated by Lipopolysaccharide-binding Protein

et al. 2006

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“…Previous studies have provided evidence that the antagonism of LPS activation through LBP/CD14/MD2/TLR4 is dependent upon the molecular class and species of phospholipid used as an antagonist (17)(18)(19)(20). We examined the molecular specificity of the POPG effect on RSV-elicited cytokine production by comparing the effects of POPG with a phospholipid counterpart containing a choline polar moiety, palmitoyl-oleoylphosphatidylcholine (POPC).…”

Section: Popg Specifically Attenuates Proinflammatory Cytokine Producmentioning

confidence: 99%

“…Additional studies have identified phosphatidylglycerol (PG) as an antagonist of LPS binding protein (LBP), and CD14 (18)(19)(20). Although PG constitutes about 10% of surfactant phospholipids, the high concentration of lipid in the extracellular surfactant layer within the alveolus, results in PG levels as high as 3.5 mg/mL This extraordinary level of PG is not found in any other tissue or mucosal surface in mammals.…”

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confidence: 99%

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

Numata

Chu

Dakhama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

161

244

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Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-γ (IFN-γ) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.antiviral | innate immunity | respiratory epithelium R espiratory syncytial virus (RSV) is an important pathogen that infects 98% of children within the first 2 years of life, and also causes serious disease in elderly individuals and persons with chronic lung disease. In the 1980s, an estimated 100,000 children were hospitalized annually with RSV infection in the United States (1). Although RSV is commonly considered a pediatric disease, it is also highlighted as an opportunistic pathogen (2), with infections producing a mortality rate of 30-100% in immunosuppressed individuals (1). There is growing appreciation that RSV is an important pathogen in elderly and high-risk patients, and a cause of acute exacerbations of asthma (3, 4) and chronic obstructive pulmonary disease (COPD) (5). Over the period 1999-2003, RSV was responsible for hospitalization rates of 10.6% for pneumonia, 11.4% for COPD, 5.4% for congestive heart failure, and 7.2% for asthma (6).No vaccine is currently available for prevention of RSV infection. Several vaccine candidates have not only proved to be ineffective, but have also been shown to lead to vaccine-enhanced disease (7,8). Inhibitors directed against the RSV fusion protein (F protein) were abandoned partly because of the frequency of resistant mutations mapping to the F gene (9). A monoclonal antibody against F protein, Palivizumab, has restricted application and it is recommended for prophylactic use during the RSV season, for high-risk infants (1). Currently the onl...

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“…TNF-␣ was determined in pooled cell-free supernatants of stimulated cells by sandwich ELISA using monoclonal mouse Ab against human TNF-␣ and HRP-conjugated rabbit anti-human TNF-␣ Ab (Intex) as stated in detail elsewhere (37). IL-8 was determined in pooled cell-free supernatants of stimulated cells by sandwich ELISA using IL-8 cytoset from Biosource exactly according to the manufacturers' protocol.…”

Section: Cytokine Determinationmentioning

confidence: 99%

MaxiK Blockade Selectively Inhibits the Lipopolysaccharide-Induced IκB-α/NF-κB Signaling Pathway in Macrophages

Papavlassopoulos¹,

Stamme²,

Thon³

et al. 2006

The Journal of Immunology

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Macrophages have a pivotal function in innate immunity against bacterial infections. They are present in all body compartments and able to detect invading microorganisms with high sensitivity. LPS (endotoxin) of Gram-negative bacteria is among the most potent stimuli for macrophages and initiates a wide panel of cellular activation responses. The release of mediators such as TNF-α and ILs is essential for the initiation of a proinflammatory antibacterial response. Here, we show that blockade of the large-conductance Ca2+-activated potassium channel MaxiK (BK) inhibited cytokine production from LPS-stimulated macrophages at the transcriptional level. This inhibitory effect of channel blockade was specific to stimulation with LPS and affected neither stimulation of macrophages with the cytokine TNF-α nor LPS-induced activation of cells that do not express MaxiK. Investigation of the upstream intracellular signaling pathways induced by LPS revealed that the blockade of MaxiK selectively inhibited signaling pathways leading to the activation of the transcription factor NF-κB and the MAPK p38, whereas activation of ERK was unaffected. We present data supporting that proximal regulation of the inhibitory factor IκB-α is critically involved in the observed inhibition of NF-κB translocation. Using alveolar macrophages from rats, we could show that the necessity of MaxiK function in activation of NF-κB and subsequent cytokine production is not restricted to in vitro-generated monocyte-derived macrophages but also can be observed in primary cells. Thus, MaxiK appears to be a central molecule in the NF-κB-dependent inflammatory response of macrophages to bacterial LPS.

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Phospholipids Inhibit Lipopolysaccharide (LPS)-Induced Cell Activation: A Role for LPS-Binding Protein

Cited by 65 publications

References 39 publications

Cell Activation of Human Macrophages by Lipoteichoic Acid Is Strongly Attenuated by Lipopolysaccharide-binding Protein

Cell Activation of Human Macrophages by Lipoteichoic Acid Is Strongly Attenuated by Lipopolysaccharide-binding Protein

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

MaxiK Blockade Selectively Inhibits the Lipopolysaccharide-Induced IκB-α/NF-κB Signaling Pathway in Macrophages

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