Downregulation of proinflammatory cytokine release in whole blood from septic patients

Ertel, Wolfgang; Kremer, Jean-Pierre; Kenney, John S.; Steckholzer, Ursula; Jarrar, Doraid; Trentz, O.; Schildberg, F. W.

doi:10.1182/blood.v85.5.1341.bloodjournal8551341

Cited by 414 publications

(127 citation statements)

References 40 publications

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“…In the present study we observed reduced cytokine production in whole blood stimulated either with LPS or with MoAbs against CD2 and CD28 following exercise, accompanied by activation of the HPA axis. A similar association between activation of the HPA axis and decreased PHA-induced proliferation of PBMC or reduced LPS-or PHA-stimulated cytokine release in whole blood ex vivo has been reported during morning peaks of cortisol circadian rhythm [19], academical stress [14], sepsis [20,21] and small cell lung cancer [22].…”

Section: Discussionsupporting

confidence: 69%

Cytokine release and its modulation by dexamethasone in whole blood following exercise

Smits

Grünberg

DeRijk

et al. 1998

Clinical and Experimental Immunology

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Glucocorticoids (GC) play an important role in the treatment of inflammatory diseases like asthma. However, in selected patients a relative resistance to GC has been reported. Recently, it has been suggested that GC sensitivity of peripheral blood leucocytes may be regulated in a dynamic fashion during exercise, in association with activation of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of the present study was to explore changes in the GC sensitivity of cytokine production by leucocytes following strenuous exercise by well trained oarsmen. These changes were studied using lipopolysaccharide (LPS)-induced and anti-CD2/anti-CD28 MoAb-stimulated cytokine release in whole blood and its modulation by dexamethasone. Following exercise, significant decreases in LPS-induced release of IL-6, tumour necrosis factor-alpha (TNF-alpha) and IL-10 and anti-CD2/anti-CD28 MoAb-stimulated secretion of interferon-gamma (IFN-gamma) were observed. In addition, the inhibitory effect of dexamethasone on both IL-6 and TNF-alpha secretion was significantly reduced following exercise, whereas that on IL-10 and IFN-gamma release was not affected. These exercise-induced changes were accompanied by activation of the HPA axis, as indicated by an increase in circulating adrenocorticotropic hormone (ACTH) levels immediately following exercise. The results from the present study suggest that GC sensitivity of whole blood cytokine release can be regulated in a dynamic fashion and that this can be assessed using an ex vivo stimulation assay. Moreover, since dexamethasone responsiveness of anti-CD2/anti-CD28 MoAb-induced IFN-gamma secretion in whole blood is not affected by exercise, it may suggest that exercise differentially affects monocytes and lymphocytes. The dynamic regulation of steroid responsiveness of leucocytes, as observed in the present study, could have important consequences for the effectiveness of GC treatment in inflammatory diseases.

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Section: Discussionsupporting

confidence: 69%

Cytokine release and its modulation by dexamethasone in whole blood following exercise

Smits

Grünberg

DeRijk

et al. 1998

Clinical and Experimental Immunology

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“…Until now, leukocytes were mainly discussed to be the source of IL-6 production in sepsis. However, a number of laboratories including our own have shown that leukocytes are severely hyporeactive in clinical sepsis and produce only low levels of this cytokine as a reaction to an adequate stimulus (19,22). This was observed at mRNA as well as protein levels.…”

Section: Discussionmentioning

confidence: 88%

Catecholamines up‐regulate lipopolysaccharide‐induced IL‐6 production in human microvascular endothelial cells

et al. 2000

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The catecholamine-mediated modulation of the cytokine network has primarily been demonstrated for leukocytes. Whereas catecholamines decrease the LPS-induced production of IL-6 by leukocytes, serum levels of IL-6 are dramatically increased by the catecholamine epinephrine in animal endotoxemia models. We now demonstrate that epinephrine as well as norepinephrine can induce IL-6 in an endothelial cell line (HMEC-1). Furthermore, these catecholamines could even potentiate the LPS-induced IL-6 protein production. The synergistic effect of catecholamines and LPS could be reproduced in primary human skin microvascular endothelial cells. The catecholamine-induced IL-6 stimulation is based on increased IL-6 mRNA levels. RNA stability assays revealed that this regulation is not a result of enhanced RNA stability and therefore is most likely due to an increased transcription. Treatment with cycloheximide indicated that new protein synthesis is not necessary for this transcriptional up-regulation of IL-6 mRNA. Preincubation with alpha and beta receptor antagonists showed that the effect is mediated by beta(1)- and beta(2)-adrenergic receptors. Thus, endothelial cells might be a possible source of increased IL-6 production observed in situations such as stress or septic shock, in which catecholamines are elevated due to endogenous production or exogenous application.

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“…Such a phenomenon is increasingly recognized in overtly septic patients, in whom in vitro hyporesponsiveness of PBMCs to potent infectious stimuli has been documented. [40][41][42] The possible source of the Gram-positive bacterial antigens implicated by our findings was of interest, given that patients with overt infection had been specifically excluded from the study. Increased fecal counts of streptococci, comparable to those of coliforms, and a high prevalence of small intestinal bacterial overgrowth with Gram-positive bacteria have been reported in patients with cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Blood Mononuclear Cell Expression of Toll–Like Receptors and Relation to Cytokine Levels in Cirrhosis

et al. 2003

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Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor ␣ (TNF-␣) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-␣ in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-␣, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-␣ production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-␣ levels, and in vitro TNF-␣ production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-␣, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-␣ and sTNFR levels. In vitro TNF-␣ production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-␣ levels were further increased and in vitro TNF-␣ production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-␣ and sTNFR levels in cirrhosis.

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Downregulation of proinflammatory cytokine release in whole blood from septic patients

Cited by 414 publications

References 40 publications

Cytokine release and its modulation by dexamethasone in whole blood following exercise

Cytokine release and its modulation by dexamethasone in whole blood following exercise

Catecholamines up‐regulate lipopolysaccharide‐induced IL‐6 production in human microvascular endothelial cells

Peripheral Blood Mononuclear Cell Expression of Toll–Like Receptors and Relation to Cytokine Levels in Cirrhosis

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