Regulation of Whole Blood Tumor Necrosis Factor Production upon Endotoxin Stimulation after Severe Blunt Trauma

Majetschak, Matthias; Flach, Regina; Heukamp, T.; Jennissen, Veronika; Obertacke, U.; Neudeck, F.; Schmit-Neuerburg, K. P.; Schade, F. Ulrich

doi:10.1097/00005373-199712000-00002

Cited by 46 publications

(34 citation statements)

References 34 publications

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“…Endotoxin tolerance has been described in bacterial LPS-pretreated macrophages as the impaired release of proinflammatory cytokines on a subsequent challenge with LPS (22). In accordance with previous findings, we demonstrated that induction of endotoxin tolerance reduced the LPS-induced expression and release of the proinflammatory cytokine IL-1␤.…”

Section: Discussionsupporting

confidence: 92%

Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Frede

Stockmann²,

Winning³

et al. 2009

The Journal of Immunology

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The oxygen-sensitive transcription factor hypoxia-inducible factor 1 (HIF-1) is known as the key regulator of hypoxia-induced gene expression. In addition to hypoxia, endotoxins such as bacterial LPS as well as proinflammatory cytokines have been shown to induce HIF-1, suggesting an integrative role for HIF-1 in conditions of hypoxia and inflammation. Cells can become tolerant to endotoxins by repetitive exposure to LPS. Herein, we studied the effect of endotoxin tolerance on HIF-1α accumulation and expression of HIF target genes in human monocytic cells and primary mouse peritoneal macrophages. Tolerant cells had reduced levels of HIF-1α under hypoxia, which was due to lowered levels of HIF-1α mRNA. HIF-1α expression is under control of NF-κB and increased DNA binding of the p52 subunit of NF-κB was found in tolerant cells. Knock down of p52 abolished the effects of endotoxin tolerance on HIF-1α expression, which suggest a negative regulatory role of p52 on HIF-1α transcription during endotoxin tolerance. Endotoxin tolerant cells showed diminished expression of the HIF target genes phosphoglycerate kinase 1 and adrenomedullin and reduced viability under hypoxic conditions, as well as a significantly reduced invasion. Peritoneal macrophages from endotoxin-tolerant mice made showed significantly reduced HIF-1α protein accumulation and subsequent HIF target gene expression. We conclude that endotoxin tolerance impairs HIF-1α induction which reduces the ability of monocytic cells to survive and function under hypoxic conditions.

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Section: Discussionsupporting

confidence: 92%

Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Frede

Stockmann²,

Winning³

et al. 2009

The Journal of Immunology

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“…These defects are illustrated by reports that stimulation of whole blood obtained from septic patients does not result in proinflammatory cytokine production (14,15,22). Several reports have also documented suppression of macrophage function following cecal ligation and puncture (4,47).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Mortality in Early and Late Sepsis

2006

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A recent hypothesis postulates that sepsis moves through different phases, with periods of enhanced inflammation alternating with periods of immune suppression. In this study we determined the levels of inflammation present during early and late septic deaths to examine whether death was due to hyperinflammation or immunosuppression. The murine model of sepsis induced by cecal ligation and puncture (CLP) was used. Complete blood counts, plasma interleukin-6 (IL-6) levels, and body weights were determined. Mice that died within the first 4 days had increased plasma levels of IL-6, indicating that there was activation of the immune system. Cecal resection on day 4 after CLP resulted in decreased abscess size, lower circulating neutrophil counts, decreased anemia, and improved survival compared to the results for mice that received only antibiotic and fluid therapy. All of the mice that died in the chronic phase of infection (after day 4) had positive peritoneal cultures containing significantly more bacteria than the cultures for surviving mice. After day 4, none of the surviving mice exhibited increases in the plasma levels of IL-6. Dying mice exhibited mixed IL-6 responses; for 41% of the mice there was never an increase in the IL-6 levels in the chronic phase, while for other mice the levels of IL-6 transiently increased prior to death. Peritoneal macrophages were obtained in the late phase of sepsis from moribund and healthy mice and were stimulated ex vivo. The cells from the moribund mice produced significantly less IL-6 than the cells obtained from healthy mice produced. These results indicate that in mice that die in the early phase there is uniformly increased inflammation. However, during the chronic phase of sepsis, some mice die with evidence of immunosuppression (increased bacterial growth and low IL-6 levels), while other mice die with immunostimulation (high IL-6 levels and bacterial growth). Determining the inflammatory status of individual patients may help guide appropriate, targeted therapy.Sepsis remains a significant clinical problem (34) despite recent advances in early goal-directed therapy (35), the use of activated protein C (6), and the use of low-dose glucocorticoids (3). A recent review of discharge records showed that there were an estimated 751,000 cases per year with an overall mortality rate of 29% (2). While in-hospital mortality has declined, the total number of deaths continues to rise due to the increased incidence of sepsis (24). There remains a critical, unmet need to better understand the basic immunopathologic alterations present in individual septic patients in order to appropriately guide therapy.Intra-abdominal infections may be a source for sepsis. These infections generate a peritoneal inflammatory response to polymicrobial organisms derived from the gastrointestinal tract (16,38). Clinical peritonitis may originate from a defect in an abdominal viscus, such as an acute intestinal perforation (49), that progresses to sepsis, resulting in high morbidity and mortality in ...

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“…It is well established that LPS-stimulated blood cytokine production is generally down-regulated after trauma (2,8,13,14,23). However, in previous studies which presented individual alterations after surgical trauma, a remarkable proportion of patients showed enhanced cytokine responses upon LPS stimulation (13,23).…”

mentioning

confidence: 98%

“…Infection, severe injuries, and major surgical trauma are known to affect cellular immune functions, which are regarded to be responsible for increased susceptibility to secondary complications, e.g., sepsis and multiple-system organ failure (8,14,19). Similar to measurements of monocytic HLA-DR expression, detection of ex vivo lipopolysaccharide (LPS)-stimulated blood cytokine responses has been widely used as an indicator of compromised host defense mechanisms following accidental or surgical trauma (1,2,3,23).…”

mentioning

confidence: 99%

“…Since the detection of distinct trauma-induced alteration patterns requires a comparison with individual leukocyte function under baseline conditions, we used blood samples from otherwise healthy patients undergoing joint replacement because of degenerative arthrosis as a clinical trauma model (3,14,23). f P values represent the levels of statistical significance for differences in autologous blood transfusion between patients with different alteration patterns.…”

mentioning

confidence: 99%

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Alterations in Leukocyte Function following Surgical Trauma: Differentiation of Distinct Reaction Types and Association with Tumor Necrosis Factor Gene Polymorphisms

Majetschak

Krehmeier

Ostroverkh

et al. 2005

Clin Vaccine Immunol

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Endotoxin-stimulated blood cytokine responses have been widely used to describe compromised host defense mechanisms after trauma. We investigated whether blood cytokine production after endotoxin stimulation is able to define distinct trauma-induced alteration patterns and whether alteration patterns are associated with tumor necrosis factor (TNF) gene polymorphisms. In 48 patients undergoing joint replacement, the levels of TNF alpha (TNF-␣), interleukin 6 (IL-6), and IL-8 production in blood after endotoxin stimulation were measured preoperatively on the day of surgery and 24 h thereafter. Patients were genotyped for the TNF-␣ position ؊308 G/A polymorphism and the TNF-␤ NcoI polymorphism. Postoperative alterations, i.e., increases or decreases of cytokine levels (TNF-␣ versus IL-6, P ‫؍‬ 0.013; TNF-␣ versus IL-8, P ‫؍‬ 0.001; IL-6 versus IL-8, P ‫؍‬ 0.007), and relative postoperative changes, i.e., percentages of preoperative cytokine levels (TNF-␣ versus IL-6, r s ‫؍‬ 0.491, P < 0.001; TNF-␣ versus IL-8, r s ‫؍‬ 0.591, P < 0.001; IL-6 versus IL-8, r s ‫؍‬ 0.474, P < 0.001 [where r s is the Spearman rank correlation coefficient]), had significant positive correlations among the cytokines. Overall enhanced postoperative alteration patterns were found in 10 patients, attenuated patterns were found in 18 patients, and mixed patterns were found in 20 patients. Preoperative cytokine production levels differed significantly between these groups (those of the overall enhanced pattern group were less than those of the mixed pattern group, which were less than those of the overall attenuated pattern group). TNF polymorphisms were not associated with overall alteration patterns, but the A*TNFB1 haplotype was associated with a postoperative increase in TNF-␣ production (P ‫؍‬ 0.042). Whole-blood cytokine responses to endotoxin define the following preexisting patterns in leukocyte function: low baseline production and overall enhanced alteration patterns after trauma (type 1), intermediate baseline production and mixed alteration patterns (type 2), and high baseline production and overall attenuated alteration patterns (type 3). TNF gene polymorphisms were associated with changes in TNF-␣ production but do not explain the overall reaction patterns of cytokine production after trauma. The clinical correlate of these newly defined reaction types remains to be determined.

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Regulation of Whole Blood Tumor Necrosis Factor Production upon Endotoxin Stimulation after Severe Blunt Trauma

Cited by 46 publications

References 34 publications

Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance

Mechanisms of Mortality in Early and Late Sepsis

Alterations in Leukocyte Function following Surgical Trauma: Differentiation of Distinct Reaction Types and Association with Tumor Necrosis Factor Gene Polymorphisms

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