Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation with lipopolysaccharide (LPS) will lead to the expression of a variety of genes in CD14+ monocytes/macrophages, but also in CD14- fibroblasts and endothelial cells. Upon secondary LPS stimulation, the expression of many of these genes is only minimal. This applies to several cytokines, most prominent among them tumor necrosis factor (TNF). Induction of tolerance appears to require some degree of activation in the primary exposure, as partial structures of LPS induce tolerance, as long as they are able to activate cells. Studies on the mechanism of unresponsiveness in tolerant cells show that the CD14 LPS receptor is not downregulated but may even increase in number at the cell surface. Furthermore, this receptor appears to be functional in that mobilization of the transcription factor NF-kappa B does still occur. This NF-kappa B complex is composed primarily of p50p50 homodimers, that bind to the respective DNA motif in the promoter region of many proinflammatory genes, thereby blocking transactivation. However, LPS tolerance does not lead to downregulation of all kinds of response, as some genes are even increased in expression upon secondary stimulation; these include p50 of NF-kappa B, TNF receptor type II and interleukin-10 (IL-10). These gene products are involved in the downregulation of proinflammatory cytokines and may thereby be instrumental in the unresponsiveness observed. Hence, tolerance to LPS is not a passive process that occurs in an exhausted cell; rather, it is a well-controlled active response that is orchestrated in order to prevent excessive inflammation. Important modulators of tolerance are glucocorticoids, which result in a general decrease of gene expression, and interferon-gamma (IFN-gamma), which enhances expression of proinflammatory genes. LPS tolerance does occur in some clinical settings, as in hemodialysis, in sepsis and in patients treated repeatedly with LPS or other monocyte activators. In fact, LPS tolerance may be exploited for prophylaxis of severe sepsis in patients at risk.
 ...
PMID:Molecular mechanism in tolerance to lipopolysaccharide. 758 50

Post-traumatic septic complications result from impaired cell-mediated immune function, which is caused in part by circulating T-cell suppressive factors (TSFs). We examined whether tumor necrosis factor alpha (TNF-alpha) antibody treatment in a baboon sepsis model influences the production of TSFs, including interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Sepsis was induced in anesthetized baboons by Escherichia coli infusion, and caused an increase in plasma levels of TNF, TSF activity, IL-10, and active TGF-beta, as well as a decrease in latent TGF-beta. TNF antibody pretreatment reduced TNF levels by 98%. Transient TSF activity (0-4 h) was only marginally influenced, while sustained TSF activity (8-24 h) was markedly reduced. TSF activity at 24 h correlated with peak TNF levels. IL-10 levels, coinciding with early TSF activity, remained unchanged by anti-TNF treatment. Levels of active TGF-beta and the drop in latent TGF-beta were decreased. We conclude that anti-TNF treatment reduces sustained TSF activity and may partially restore impaired cell-mediated immune function.
 ...
PMID:Tumor necrosis factor antibody treatment of septic baboons reduces the production of sustained T-cell suppressive factors. 777 95

Interleukin-10 is produced during incubation of human whole blood with bacterial lipopolysaccharide (LPS) and down-regulates tumour necrosis factor-alpha production in this in-vitro model of endotoxaemia. 39 out of 69 (57%) patients with gram-negative (n = 25) or gram-positive septicaemia (n = 44) had increased plasma interleukin-10 (range 12-2740 pg/mL), whereas interleukin-10 was undetectable in 29 out of 33 control patients without infection and in 20 healthy volunteers. Patients with septic shock (n = 21) had higher interleukin-10 (main 58 pg/mL) than septicaemic patients without shock (11 pg/mL, p < 0.001). We conclude that interleukin-10 is produced during sepsis and might be involved in the control of the inflammatory response induced by bacterial products.
 ...
PMID:Interleukin-10 production during septicaemia. 790 83

We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis.
 ...
PMID:Interleukin-10 protects neonatal mice from lethal group B streptococcal infection. 869 23

Exposure to endotoxin produces a state of macrophage hyporesponsiveness on subsequent stimulation. Monocytes in patients with septic shock demonstrate a similar hyporesponsiveness to endotoxin. The purpose of this study was to examine whether this state of hyporesponsiveness extends to other inflammatory stimuli and the relationship of this state to cell surface receptor expression and the release of anti-inflammatory cytokines. Twelve normal volunteers, 10 patients with severe sepsis, and 9 patients with septic shock were included in the study. Monocytes from each subject were isolated and stimulated with lipopolysaccharide (LPS), staphylococcal enterotoxin B (SEB), and phorbol myristate acetate (PMA). Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured in the supernatants by enzyme-linked immunosorbent assay (ELISA). Serum levels of transforming growth factor-beta1 (TGF-beta1), prostaglandin E2 (PGE2), and interleukin-10 (IL-10) were also measured by ELISA. The expression of monocyte CD14 and HLA-DR in whole blood were measured by flow cytometry. Patients with septic shock demonstrated significantly decreased TNF-alpha and IL-1beta release as compared with normal subjects in response to LPS. In response to SEB, patients with sepsis and patient with septic shock demonstrated significantly decreased release of TNF-alpha and IL-1beta. Significant decreases in TNF-alpha release were found in the patients with septic shock after PMA stimulation. There were no significant differences in the monocyte response to the different stimuli between patients with gram-positive sepsis and gram-negative sepsis. HLA-DR expression was significantly decreased in patients with septic shock (58 +/- 9 fluorescence units (flU)) as compared with normal subjects (102 +/- 14 flU) (p < 0.05). No differences in CD14 expression were observed. IL-10 levels were significantly increased in patients with sepsis (16 +/- 4 pg/ml) and in patients with septic shock (42 +/- 15 pg/ml) and were detectable in 1 normal subject. TGF-beta1 levels were decreased in patients with septic shock (25 +/- 6 pg/ml) as compared with those in normal subjects (37 +/- 2 pg/ml)(p < 0.05). PGE2 levels were significantly increased in patients with septic shock and patients with sepsis. These data are consistent with a more generalized monocyte hyporesponsiveness to bacterial toxins that may be related to altered cell surface receptor expression and the release of anti-inflammatory cytokines.
 ...
PMID:Monocyte response to bacterial toxins, expression of cell surface receptors, and release of anti-inflammatory cytokines during sepsis. 896 Jun 43

The complex pathway seen in patients with the systemic inflammatory response syndrome (SIRS) does not readily respond to mediator blockade. All such trials conducted in SIRS patients have shown no benefit in reducing mortality. We have shown experimentally that in sepsis, the administration of beta 2-adrenoceptor agonists reduces hepatic cellular injury, whereas administration of an alpha 1-adrenoceptor agonist increases hepatic cellular injury. Inflammatory mediators can cause a dose-related reversible change in target endothelial cells (ECs). There is a substantial body of literature describing the anti-inflammatory effects of beta 2-adrenoceptor agonists. They reduce both the increased permeability and the production of inflammatory mediators from ECs. Cellular transduction processes are involved when adrenergic receptor agonists modify either the anti-inflammatory or proinflammatory response to sepsis in ECs. Inflammatory mediators and alpha 1-adrenoceptor agonists stimulate their trimeric G protein-linked receptors to produce diacylglycerol (DAG) and increase the intracellular concentration of calcium. DAG is involved in the production of both inflammatory proteins and lipids. In addition, mitogen-activated protein kinase (MAPK) is activated which is also involved in the production of inflammatory proteins and lipids. beta 2-adrenoceptor agonists activate their trimeric G protein-linked receptors to produce the stimulatory G protein (Gs). Gs stimulates adenyl cyclase to form cyclic adenosine monophosphate (cAMP) and activate protein kinase A (PKA). PKA is involved in activating gene transcription agents to produce anti-inflammatory proteins such as interleukin-10. PKA also inhibits phospholipase C and MAPK. Although promising, the use of beta-adrenoceptor agonists or agonists that increase cellular cAMP to activate the cells' endogenous anti-inflammatory pathway requires further study.
 ...
PMID:Cell surface adrenergic receptor stimulation modifies the endothelial response to SIRS. Systemic Inflammatory Response Syndrome. 896 76

Monophosphoryl lipid A (MPL) is a nontoxic derivative of the lipid A region of lipopolysaccharide (LPS) that is being developed as both an adjuvant and prophylactic drug for septic shock. We compared the ability of LPS and MPL to induce interleukin-10 (IL-10), IL-12 p35, IL-12 p40, gamma interferon (IFN-gamma), glucocorticoid receptor (GR), IL-1 receptor antagonist (IL-1ra), and inducible nitric oxide synthase mRNA expression in murine peritoneal macrophages. These genes were chosen for their ability to positively or negatively regulate the host immune response and thus for their potential involvement in MPL-induced adjuvanticity or in its ability to protect against sepsis. LPS was a more potent inducer of IL-12 p35, IL-12 p40, and IFN-gamma mRNA, as well as of IL-12 protein, than MPL. In contrast, MPL induced higher levels of IL-10 mRNA than did LPS from 1 to 1,000 ng/ml. In general, MPL was not a more potent inducer of negative regulatory genes, since MPL and LPS induced similar levels of GR and IL-1ra mRNA. Addition of anti-IL-10 antibody to cultures increased the induction of MPL-induced IL-12 p35, IL-12 p40, and IFN-gamma mRNA, suggesting that the enhanced production of IL-10 by MPL-stimulated macrophages contributes to decreased production of mRNA for IL-12 (p35 and p40) and IFN-gamma. Conversely, the addition of exogenous IL-10 to LPS-treated macrophages reduced the mRNA expression of these cytokine genes. These studies suggest that enhanced production of IL-10 by MPL-stimulated macrophages may contribute to the reduced toxicity of MPL through its negative action on induction of cytokines shown to enhance endotoxicity.
 ...
PMID:Lipopolysaccharide and monophosphoryl lipid A differentially regulate interleukin-12, gamma interferon, and interleukin-10 mRNA production in murine macrophages. 923 81

Cytokines may play an important role in the pathophysiology of traumatic brain injury (TBI) in children. Interleukin-6 (IL-6) is a proinflammatory cyotkine that plays a role in regenerative processes within the central nervous system (CNS), whereas interleukin-10 (IL-10) is an antiinflammatory cytokine. Both have been measured in serum and cerebrospinal fluid (CSF) as an index of the degree of inflammation in diseases, including sepsis and meningitis. We hypothesized that both IL-6 and IL-10 would be increased in the CSF of children after severe TBI. Fifteen children who sustained severe TBI (Glascow Coma Score [GCS] < or = 7) were studied. Standard neurointensive care was provided. Ventricular CSF collected the first 3 days after TBI was analyzed for IL-6 and IL-10 concentrations by ELISA. Controls were 20 children who were evaluated for meningitis with diagnostic lumbar puncture subsequently found to have no CSF pleocytosis and negative cultures. IL-6 was increased in children after TBI versus controls on all days studied (day 1, 3158.2 +/- 621.8 pg/ml; day 2, 1111.6 +/- 337.0 pg/ml; day 3, 826.7 +/- 193.5 pg/ml vs. 20.6 +/- 5.8 pg/ml, p < 0.0001, Mann-Whitney Rank Sum). IL-10 was increased in children after TBI vs controls on all days studied (day 1, 47.2 +/- 12.9 pg/ml; day 2, 21.0 +/- 6.7 pg/ml; day 3, 15.5 +/- 5.9 pg/ml vs. 8.9 +/- 7.5 pg/ml, p < 0.01). Increased IL-10 concentrations were independently associated with age < 4 years and mortality (p = 0.004 and 0.04, respectively, multivariate linear model). This study demonstrates that IL-6 is increased after TBI in children to levels similar to those reported in adults and is the first to show that IL-10 is increased in CSF of humans after TBI. These data suggest that there may be an age-dependent production of IL-10 after TBI in children.
 ...
PMID:Interleukin-6 and interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children. 925 63

We hypothesized that chemokines may play important roles in a cecal ligation and puncture (CLP) model of septic peritonitis in CD-1 mice. Concentrations of C-X-C (macrophage inflammatory protein 2 [MIP-2] and ENA-78) and C-C (MIP-1alpha and JE) chemokines were measured (by enzyme-linked immunosorbent assay) in serum, peritoneal lavage fluid, lung, and liver at 4, 8, 24, 48, and 96 h after CLP. Significant elevations in all measured chemokines occurred in peritoneal fluid after CLP (P < 0.05). MIP-2, in particular, increased dramatically (>400-fold, P < 0.001) in peritoneal fluid, serum, and to a lesser extent lung and liver (P < 0.05). Increased MIP-2 was correlated with severity of sepsis (P < 0.001). To determine the significance of this finding, mice were passively immunized prior to CLP with polyclonal antibody to MIP-2, which decreased mortality from 85 to 38% at 96 h (P < 0.01). To further understand the mechanism of the effect of MIP-2, additional measurements demonstrated that anti-MIP-2 prior to CLP decreased the percent neutrophils in peritoneal fluid (55% +/- 12%, compared with 82% +/- 10% in controls), but no significant changes in tumor necrosis factor alpha, interleukin-6, or interleukin-10 occurred. MIP-2 contributes to the inflammatory response and overall mortality in this model of severe septic peritonitis, possibly by increasing recruitment of neutrophils, which clear bacteria but may also injure the host.
 ...
PMID:Elevated levels of macrophage inflammatory protein 2 in severe murine peritonitis increase neutrophil recruitment and mortality. 928 62

To systematically elucidate the gene expression of inflammatory and immune modulators following middle cerebral artery occlusion (MCAO) in the rat, we studied interleukin-10 (IL-10) along with tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-2 (IL-2). Gene expression of these cytokines was studied ipsilateral and contralateral to the MCAO, with mRNA expression levels evaluated 2, 4, 6, 8 and 12 h following permanent MCAO by reverse transcriptase polymerase chain reaction (RT-PCR). In the ischemic hemisphere TNF-alpha and IL-1beta mRNA increased at 2 h following MCAO and peaked at 6 h, with IL-10 mRNA detected only at 6 h. Contralaterally, both TNF-alpha and IL-1beta mRNAs were expressed with a similar pattern to that in the ischemic hemisphere, but at lower levels, with no contralateral IL-10 expression. There was no difference in IL-2 gene expression between control and experimental animals in either hemisphere. These results demonstrate that IL-10 and TNF-alpha, IL-1beta gene expression is induced early following MCAO. The temporal profile of these cytokines is similar to that seen in sepsis, where TNF-alpha induces IL-10; subsequently IL-10 inhibits TNF-alpha expression. The similarity of the temporal profile of cytokine expression in sepsis and cerebral ischemia suggests that IL-10 should be studied as a potential inhibitor of TNF-alpha production in ischemic brain tissue. The factors inducing contralateral expression of the inflammatory cytokines, TNF-alpha and IL-1beta, along with the potential clinical significance of this remote cytokine gene expression, merit further study.
 ...
PMID:Gene expression of IL-10 in relationship to TNF-alpha, IL-1beta and IL-2 in the rat brain following middle cerebral artery occlusion. 941 30


1 2 3 4 5 6 7 8 9 10 Next >>