Induction of tumor necrosis factor, IFN-gamma, and acute lethality in mice by toxic and non-toxic forms of lipid A.

Kiener, Peter A.; Marek, Frederick M.; Rodgers, Gemma; Lin, Po-Han; Warr, Glenn A.; Desiderio, J. V.

doi:10.4049/jimmunol.141.3.870

Cited by 87 publications

(1 citation statement)

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“…10 Monophosphoryl lipid A (MPL) is an effective immune stimulant and has been used as an approved adjuvant for human and animal vaccines for many years. [11][12][13][14][15] MPL is a less-toxic, TLR4 agonist developed as an alternative to lipopolysaccharide (LPS), a highly inflammatory compound produced by gram-negative bacteria. Novel lipid A mimetic compounds have also been synthesized as alternatives to MPL.…”

Section: Introductionmentioning

confidence: 99%

A TLR4 agonist liposome formulation effectively stimulates innate immunity and enhances protection from bacterial infection

et al. 2023

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Stimulation of innate immunity can protect against infectious insult and could be used in combination with other therapies. Since antibiotic resistance is an increasing concern, strategies to reduce the dose or eliminate the need for these drugs are warranted. Lipo-CRX is a formulation in which the TLR4 agonist CRX-527 is incorporated into lipid membranes in liposomes. Lipo-CRX is less inflammatory than either CRX-527 or LPS, but retains unique capacity to enhance host defense responses. We compared lipo-CRX to other agonists in vitro using mammalian cells and in vivo in mice, and assessed indicators of innate immune responses and protection from bacterial infection. Lipo-CRX is similar to E. coli LPS in its capacity to activate bovine γδ T cells and to recruit neutrophils into mouse lungs, but with less reactivity in the LAL assay. However, lipo-CRX uniquely induced the production of systemic innate immune cytokines. In the mouse model of brucellosis, delivery of lipo-CRX to the lungs reduced the dissemination of B. abortus. While lipo-CRX or the antibiotic ampicillin alone did not alter B. abortus burdens in the lung, the combination had a synergistic beneficial effect. Our data suggest that stimulating the innate immune system with lipo-CRX, either alone or when combined with antibiotics, can enhance bacterial clearance in the mouse model of brucellosis.

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Section: Introductionmentioning

confidence: 99%

A TLR4 agonist liposome formulation effectively stimulates innate immunity and enhances protection from bacterial infection

et al. 2023

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Tumor Necrosis Factor Alone Does Not Explain the Lethal Effect of Lipopolysaccharide

Sánchez-Cantú

Rode²,

Yun³

et al. 1991

Arch Surg

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Lethality and tumor necrosis factor production induced by different types of lipopolysaccharide were studied in naive (non-primed) rats during the late phase of endotoxin tolerance. The correlation with antilipopolysaccharide antibodies was also analyzed. No correlation was found between tumor necrosis factor levels and lipopolysaccharide-induced mortality in naive animals. Low-toxicity lipopolysaccharide preparations induced levels of tumor necrosis factor similar to those induced with more toxic types of lipopolysaccharide. Late tolerance was associated with progressively lower levels of lipopolysaccharide-induced tumor necrosis factor and increasing titers of antilipopolysaccharide antibodies after repeated injections of homologous lipopolysaccharide. During late endotonxin tolerance, a direct correlation between the lipopolysaccharide dose and peak tumor necrosis factor serum levels was found. We conclude that since tumor necrosis factor serum levels do not correlate with mortality, tumor necrosis factor alone cannot explain the lethal effect of lipopolysaccharide.

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The acute-phase response protects mice from D-galactosamine sensitization to endotoxin and tumor necrosis factor-α

1992

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D-Galactosamine is an hepatocyte-specific inhibitor of RNA synthesis. It has been used to sensitize animals both to the lethal effects of bacterial endotoxin (lipopolysaccharide) and to a principal lipopolysaccharide-induced mediator of shock, tumor necrosis factor-alpha. The mechanism by which this sensitization occurs is unknown. Because lipopolysaccharide, acting through a network of cytokines, provokes the transcription of a number of hepatic acute-phase proteins, we postulated that the lipopolysaccharide-sensitizing effect of D-galactosamine could be caused by its inhibition of acute-phase product transcription. We confirmed that the acute-phase response to lipopolysaccharide was attenuated by simultaneous administration of D-galactosamine. However, when the acute-phase response was induced by subcutaneous turpentine 24 hr before D-galactosamine administration, the effect of D-galactosamine on circulating acute-phase reactants was negligible. Furthermore, induction of an a priori acute-phase response protected mice from both D-galactosamine/lipopolysaccharide and D-galactosamine/tumor necrosis factor-alpha-induced death. The turpentine-induced acute-phase response did not decrease endogenous tumor necrosis factor-alpha production after lipopolysaccharide, nor did it affect the clearance of larger doses of injected tumor necrosis factor-alpha. Thus we suggest that the acute-phase response protects against death in D-galactosamine-sensitized mice through an interaction with mediators of shock subsequent to tumor necrosis factor-alpha release.

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Induction of tumor necrosis factor, IFN-gamma, and acute lethality in mice by toxic and non-toxic forms of lipid A.

Cited by 87 publications

References 0 publications

A TLR4 agonist liposome formulation effectively stimulates innate immunity and enhances protection from bacterial infection

A TLR4 agonist liposome formulation effectively stimulates innate immunity and enhances protection from bacterial infection

Tumor Necrosis Factor Alone Does Not Explain the Lethal Effect of Lipopolysaccharide

The acute-phase response protects mice from D-galactosamine sensitization to endotoxin and tumor necrosis factor-α

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