Endotoxins And Disease Mechanisms

Morrison, David C.

doi:10.1146/annurev.med.38.1.417

Cited by 514 publications

(452 citation statements)

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“…The phenomenon of LPS desensitization to its own action, frequently referred to as tolerance to LPS [1,11,24,25], can be induced following natural infection of patients with Gramnegative bacteria, or experimentally by the administration of low doses of LPS [3,12,26]. Endotoxin tolerance is neither a mechanism of cell anergy induction nor a passive process that occurs in an exhausted cell (macrophage).…”

Section: Discussionmentioning

confidence: 99%

“…Severe Gram-negative infections in humans can result in endotoxic shock, which is the most common cause of death in intensive care units [1][2][3]. Most of the toxic effects caused by Gram-negative bacteria have been ascribed to lipopolysaccharide (LPS), a normal constituent of the bacterial wall [1,2,4].…”

Section: Introductionmentioning

confidence: 99%

“…Most of the toxic effects caused by Gram-negative bacteria have been ascribed to lipopolysaccharide (LPS), a normal constituent of the bacterial wall [1,2,4].…”

Section: Introductionmentioning

confidence: 99%

“…When local infection develops into sepsis, a strong systemic reaction occurs, and cytokines normally restricted to areas of local injury can be detected systemically, causing symptoms of septic shock [2,4,5]. This systemic inflammation is frequently initiated by the activation of monocytes after LPS exposure, with a sequential release of different cytokines such as tumour necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-12, IL-6, interferon-g (IFN-g) and IL-8 [1,6].…”

Section: Introductionmentioning

confidence: 99%

“…Although acute endotoxic shock has been largely considered a consequence of the early pro-inflammatory events induced by LPS [1][2][3], less attention has been paid to the subsequent antiinflammatory effects induced by endotoxins. Despite the fact that host mechanisms responsible for LPS tolerance are not well understood, they seem to be crucial for patients with sepsis [3].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Alves-Rosa

Vulcano

Beigier-Bompadre

et al. 2002

Clinical and Experimental Immunology

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SUMMARYEndotoxin or lipopolysaccharide (LPS) tolerance may be partially due to the secretion of potent antiinflammatory cytokines following severe Gram-negative infections, or by low doses of LPS. In this work, we describe the effects of interleukin-1b (IL-1b) and tumour necrosis factor alpha (TNF-a), two early cytokines secreted after LPS exposure, in the induction of LPS tolerance. Our results demonstrate that mice treated with three daily doses of 100 ng of IL-1b were tolerant to LPS-induced shock. However, TNF-a was unable to induce an LPS refractory state. Given the fact that 100 ng of IL-1b increase the plasma levels of glucocorticoids, we evaluated whether a daily injection of dexamethasone (DEX) alone was able to reproduce the LPS-like tolerant state. However, no signs of LPS refractoriness were detected, except when DEX was administered concomitantly with a dose of IL-1b that does not induce corticosterone secretion (12 ng/mouse). This dose was found to induce in vitro up-regulation of the glucocorticoid receptors (GcR) of peritoneal macrophages following 24 h of treatment. In addition, we demonstrate that IL-1b is capable of inducing the down-regulation of Toll-like receptor 4 (TLR4), a crucial molecule in the signal transduction of LPS. Taken together, our results indicate that IL-1b can generate tolerance to LPS in vivo, and suggest that the regulation of mechanisms of the downregulation of TLR4, as well as those involved in the expression of GcR and/or in the secretion of glucocorticoids, would be crucial for these effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Most of the toxic effects caused by Gram-negative bacteria have been ascribed to lipopolysaccharide (LPS), a normal constituent of the bacterial wall [1,2,4].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Alves-Rosa

Vulcano

Beigier-Bompadre

et al. 2002

Clinical and Experimental Immunology

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Inhibition of Splenic Macrophage Tumor Necrosis Factor α Secretion In Vivo by Antilipopolysaccharide Monoclonal Antibodies

Battafarano

Burd

Kurrelmeyer³

et al. 1994

Arch Surg

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These results strongly support the contention that inhibition of LPS-induced TNF-alpha secretion at both the tissue and systemic levels is a key mechanism by which anti-LPS mAbs provide protection during gram-negative bacterial peritonitis. We believe that in vivo monitoring of macrophage cytokine secretion will be critical for elucidating the precise role of a variety of mediators in the pathogenesis of gram-negative bacterial sepsis.

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