Inhibitory Effect of a Phosphatidyl Ethanolamine Derivative on LPS-Induced Sepsis

Lee, Chunghyun; An, Hyun‐Jung; Kim, Jung-ln; Lee, Hayyoung; Paik, Sang‐Gi

doi:10.1007/s10059-009-0049-4

Cited by 12 publications

(13 citation statements)

References 18 publications

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“…As serum and sCD14 did not modify responses to ExoS, we questioned whether this might reduce the potential therapeutic efficacy of lipid-based TLR antagonists known to interfere with binding of LPS to LBP or CD14. If this were true, lipidbased agents such as OxPAPC and PE-DTPA, which are known to compete with LPS for binding to soluble and membranebound adaptor molecules, would not inhibit responses to ExoS [55][56][57]. As expected, both agents inhibited the response to LPS (Fig.…”

Section: Figure 5 Expression Of Cd14 On U373 Cells Enhances Binding Tosupporting

confidence: 51%

Membrane CD14, but not soluble CD14, is used by exoenzyme S fromP. aeruginosato signal proinflammatory cytokine production

Berenger

Hamill

Stack

et al. 2011

Journal of Leukocyte Biology

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Recognition of TLR agonists involves a complex interplay among a variety of serum and cell membrane molecules, including mCD14 and sCD14 that is not fully understood. TLR activation results in downstream signaling that induces inflammatory cytokine production in response to pathogenic molecules, such as ExoS, which is a TLR2 and TLR4 agonist produced by the opportunistic pathogen Pseudomonas aeruginosa. We reasoned that responses to ExoS, a protein, might differ from canonical TLR agonists such as LPS. Stimulating the expression of mCD14 with vitamin D3 enhanced the response to ExoS and LPS. Also, blocking anti-CD14 antibody or removing mCD14 using PLC reduced responses to ExoS and LPS. Furthermore, CD14-deficient cells were unable to bind and respond to ExoS, which was restored by stable transfection of mCD14, indicating that mCD14 was required for the response to ExoS. However, addition of sCD14 to culture enhanced responsiveness to LPS but not ExoS. Moreover, the addition of serum did not alter the response to ExoS but enhanced the response to LPS. Despite differences of adaptor molecule use between ExoS and LPS, lipid antagonists that compete for LPS binding to CD14 also inhibited the response to ExoS. These results highlight a fundamental difference between TLR agonists in their requirements for CD14 and serum components. These results suggest that understanding the dissimilarities and targeting overlapping sites of interaction on CD14 may yield a synergistic, clinical benefit during infections where a variety of TLR agonists are present.

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Section: Figure 5 Expression Of Cd14 On U373 Cells Enhances Binding Tosupporting

confidence: 51%

Membrane CD14, but not soluble CD14, is used by exoenzyme S fromP. aeruginosato signal proinflammatory cytokine production

Berenger

Hamill

Stack

et al. 2011

Journal of Leukocyte Biology

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“…Our findings suggest that CD38 is solubilized by MMP-9 in certain conditions such as inflammation. LPS is a main mediator of inflammation in bacterial infection (Lee et al, 2009). Accordingly, CD38 knockout mice were shown to be more sensitive to bacterial infection than their wild-type counterparts (Partida-Sanchez et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Induces CD38 Expression and Solubilization in J774 Macrophage Cells

Lee

Song

Yoo

et al. 2012

Molecules and Cells

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*CD38, an ADP ribosyl cyclase, is a 45 kDa type II transmembrane protein having a short N-terminal cytoplasmic domain and a long C-terminal extracellular domain, expressed on the surface of various cells including macrophages, lymphocytes, and pancreatic β cells. It is known to be involved in cell adhesion, signal transduction and calcium signaling. In addition to its transmembrane form, CD38 is detectable in biological fluids in soluble forms. The mechanism by which CD38 is solubilized from the plasma membrane is not yet clarified. In this study, we found that lipopolysaccharide (LPS) induced CD38 upregulation and its extracellular release in J774 macrophage cells. Furthermore, it also increased CD38 expression at the mRNA level by activating the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. However, LPS decreased the levels of CD38 in the plasma membrane by releasing CD38 into the culture supernatant. LPS-induced CD38 release was blocked by the metalloproteinase-9 inhibitor indicating that MMP-9 solubilizes CD38. In conclusion, the present findings demonstrate a potential mechanism by which C38 is solubilized from the plasma membrane.

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“…A synthetic phospholipid analogue, the cationic amphiphile 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-diethyle-netriaminepentaacetic acid (also known as PE-DTPA, Figure 5 ), improved the survival of LPS-treated C57BL/6 mice in a dose-dependent manner, as compared with group of animals given LPS alone [ 133 ].…”

Section: Synthetic Tlr4 Antagonistsmentioning

confidence: 99%

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

et al. 2017

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Toll-Like Receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders that are becoming more and more frequent in developed countries. Modulation of the TLR4 pathway is a potential strategy to specifically target these pathologies. Among the diseases caused by TLR4 abnormal activation by bacterial endotoxin, sepsis is the most dangerous one because it is a life-threatening acute system inflammatory condition that still lacks specific pharmacological treatment. Here, we review molecules at a preclinical or clinical phase of development, that are active in inhibiting the TLR4-MyD88 and TLR4-TRIF pathways in animal models. These are low-molecular weight compounds of natural and synthetic origin that can be considered leads for drug development. The results of in vivo studies in the sepsis model and the mechanisms of action of drug leads are presented and critically discussed, evidencing the differences in treatment results from rodents to humans.

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Inhibitory Effect of a Phosphatidyl Ethanolamine Derivative on LPS-Induced Sepsis

Cited by 12 publications

References 18 publications

Membrane CD14, but not soluble CD14, is used by exoenzyme S fromP. aeruginosato signal proinflammatory cytokine production

Membrane CD14, but not soluble CD14, is used by exoenzyme S fromP. aeruginosato signal proinflammatory cytokine production

Lipopolysaccharide Induces CD38 Expression and Solubilization in J774 Macrophage Cells

TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis

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