Macrophage Endotoxin Tolerance: Effect of TNF or Endotoxin Pretreatment

Li, Mary H.; Seatter, Susan C.; Manthei, Robin; Bubrick, Melvin P.; West, Michael A.

doi:10.1006/jsre.1994.1115

Cited by 50 publications

(21 citation statements)

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“…In vitro models of M LPS tolerance have also failed to reproduce the tolerance caused by LPS pretreatment by giving exogenous TNF. 6 Other in vitro models of LPS tolerance have found associated increases in IL-10 and prostaglandin E 2 , both of which have antiinflammatory properties. 6,22 Whether the induction of the tolerant state in our model is modulated by inhibition of proinflammatory mediators or the production of counterinflammatory mediators such as IL-10 or prostaglandin E 2 has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Tolerance to Shock: An Exploration of Mechanism

Mendez¹,

Kramer²,

Salhab³

et al. 1999

Annals of Surgery

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Section: Discussionmentioning

confidence: 99%

Tolerance to Shock: An Exploration of Mechanism

Mendez¹,

Kramer²,

Salhab³

et al. 1999

Annals of Surgery

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“…Tolerance, a term used to describe reduced cellular responsiveness to a stimulus, can be induced in mononuclear cells by pretreating cells with endotoxin (16). Pretreatment results in inhibition of MAPK and TNF-␣ production to subsequent endotoxin exposure (17).…”

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confidence: 99%

Hypertonic Preconditioning Inhibits Macrophage Responsiveness to Endotoxin

Cuschieri

Gourlay

Garcia

et al. 2002

The Journal of Immunology

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Hypertonic saline has been shown to modulate cell shape and the response of components of the innate immune response. However, the effect of hypertonic saline on the macrophage remains unknown. We hypothesized that hypertonic preconditioning would impair subsequent inflammatory mediator signaling through a reduction in stress fiber polymerization and mitogen-activated protein kinase activity after LPS stimulation. Rabbit alveolar macrophages were stimulated with 100 ng/ml of LPS. Selected cells were preconditioned with 40–100 mM of NaCl, mannitol, or urea for 4 h and returned to isotonic medium before LPS stimulation. Cellular protein was harvested and subjected to Western blot analysis for the dually phosphorylated active forms of p38 and extracellular signal-related kinase (ERK) 1/2. TNF production was determined by an L929 bioassay, and stress fiber polymerization was evaluated by confocal microscopy. Preconditioning of macrophages with NaCl or mannitol resulted in dose-dependent reduction in ERK 1/2 phosphorylation with no effect on p38 phosphorylation. Urea preconditioning had no effect on either mitogen-activated protein kinase. A dose-dependent attenuation of TNF production was seen with NaCl and mannitol preconditioning (p < 0.05), but not with urea. NaCl and mannitol preconditioning resulted in failure of LPS-induced stress fiber polymerization, whereas urea did not. Extracellular hypertonic conditions (i.e., NaCl and mannitol) have an immunomodulatory effect on macrophages, demonstrated through failure of optimal stress fiber polymerization, ERK 1/2 activity, and TNF production. Intracellular hypertonic conditions (i.e., urea) had no significant effect. Hypertonic saline or mannitol resuscitation, therefore, may help protect against multiple-organ dysfunction syndrome as a result of this reduced proinflammatory responsiveness.

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“…We next looked at TNF-a as an inducer of tolerance. The current dogma is that TNF-a is not capable of tolerance induction [20,21]. This is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, despite early in vivo adult work demonstrating evidence of TNF-a tolerance induction using end points of survival and weight loss [49][50][51], more recent ex vivo studies have failed to demonstrate any role for this cytokine in tolerance induction [20,52,53].…”

Section: Discussionmentioning

confidence: 99%

TNF-α is a mediator of the anti-inflammatory response in a human neonatal model of the non-septic shock syndrome

2005

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The anti-inflammatory/immunoparalytic phase of the systemic inflammatory response syndrome (SIRS) following major insult (surgery, thermal/traumatic injury) is of major clinical importance in the neonate, during which the risk of infection is particularly great. Here, the mechanisms by which TNF-a production is suppressed in response to infection are largely unknown. We questioned whether TNF-a itself could be a critical mediator of this suppression. Monocytes, isolated from cord blood (n=3), were treated with LPS (100 ng/ml), TNF-a (10 ng/ml, +/À anti-TNF-a antibody) for 18 and 36 h. Cells were then restimulated with LPS (Gram Àve) or Pam-3-Cys (Gram +ve) for 24 h. This was also done in the presence of selective inhibitors of MAP kinases p38, MEK and JNK. TNF-a, IL-6, IL-10 and IL-8 were quantified by ELISA CD86 and HLA-DR expression were determined flow cytometrically. Cells stimulated with LPS for 24 h produced TNF-a (282 pg/ ml), IL-10 (1,236 pg/ml), IL-6 (2,694 pg/ml) and IL-8 (2,144 pg/ml). In cells pre-exposed to TNF-a for 36 h, there was a significant suppression in TNF-a and IL-6 levels (9 and 221 pg/ml, respectively) (P<0.05) with minimal impact on IL-10 (1,206 pg/ml) and IL-8 levels (1,886 pg/ml). A similar effect was seen with Pam-3-Cys with a tenfold decrease in levels of TNF-a and IL-6 (86 fi 8.5 pg/ml and 458 fi 46 pg/ml, respectively) with no effect on IL-10 and IL-8 levels. Anti-TNF-a antibody negated this effect. Inhibition of p38 kinase reversed the TNF-a effect. Inhibition of the JNK and MEK kinases had no effect. A reduction in the expression of CD86 and HLA-DR was observed. This ex-vivo model of non-septic SIRS demonstrates that TNF-a, released during a major insult, can suppress subsequent monocyte responses to bacterial agents through p38 MAP kinase, making it a potential therapeutic target.

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Macrophage Endotoxin Tolerance: Effect of TNF or Endotoxin Pretreatment

Cited by 50 publications

References 0 publications

Tolerance to Shock: An Exploration of Mechanism

Tolerance to Shock: An Exploration of Mechanism

Hypertonic Preconditioning Inhibits Macrophage Responsiveness to Endotoxin

TNF-α is a mediator of the anti-inflammatory response in a human neonatal model of the non-septic shock syndrome

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