Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombopoietin (TPO) and its receptor (TPOR) are expressed in the central nervous system (CNS). Although TPO shares significant homology with various neurotrophins, recent data indicate a proapoptotic function of TPO in the CNS. In this study, TPO concentrations were analyzed in the cerebrospinal fluid (CSF) of neonates. Human neuroblastoma-derived SH-SY5Y cells were established to elucidate the effects of inflammation and hypoxia on neuronal Tpo expression. TPO was detectable in the CSF of 6 of 15 neonates with bacterial infection/sepsis (median 140, range 2-613 pg/mL), 5 of 9 neonates with posthemorrhagic hydrocephalus (median 31, range 1.4-469 pg/mL), 3 of 4 neonates with posthemorrhagic hydrocephalus plus bacterial infection/sepsis or meningitis (median 97, range 6-397 pg/mL), but not in controls ( n = 3). Neither the presence of detectable TPO nor its level in the CSF significantly correlated with any clinical or laboratory parameter. In SH-SY5Y cells, TPO and TPOR expression was detected by RT-PCR and Western blot analysis. In vitro, interleukin-6 (IL-6) did not significantly change Tpo gene expression. In contrast, Tpo mRNA expression significantly decreased under hypoxia, whereas erythropoietin (EPO) mRNA expression increased. In conclusion, our data provide evidence that in neuronal cells, TPO production is regulated by different mechanisms than in hepatocytes.
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PMID:High thrombopoietin concentrations in the cerebrospinal fluid of neonates with sepsis and intraventricular hemorrhage may contribute to brain damage. 1731 41

The contribution of bacterial infection to tumorigenesis is usually ascribed to infection-associated inflammation. An alternate view is that direct interaction of bacteria with tumor cells promotes tumor progression. Here, we show that the microenvironment of large tumors favors bacterial survival, which in turn directly accelerates tumor growth by activating tumor cell Toll-like receptors (TLR). Listeria monocytogenes (Lm) survives in the microenvironment of large but not small tumors, resulting in the promotion of tumor growth. Lm did not affect the percentage of regulatory T cells or myeloid suppressor cells in the tumor. Through TLR2 signaling, Lm activated mitogen-activated protein kinases and nuclear factor-kappaB in tumor cells, resulting in the increased production of nitric oxide and interleukin-6 and increased proliferation of tumor cells. All of these effects were abrogated by silencing expression of TLR2, but not TLR4. The interaction of Helicobacter pylori with tumor cells from gastric carcinoma patients resulted in similar effects. These findings provide a new insight into infection-associated tumorigenesis and illustrate the importance of antibiotic therapy to treat tumors with bacterial infiltration.
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PMID:Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. 3141 50

AvrA is a newly described bacterial effector existing in Salmonella. Here, we test the hypothesis that AvrA is a deubiquitinase that removes ubiquitin from two inhibitors of the nuclear factor-kappaB (NF-kappaB) pathway, IkappaBalpha and beta-catenin, thereby inhibiting the inflammatory responses of the host. The role of AvrA was assessed in intestinal epithelial cell models and in mouse models infected with AvrA-deficient and -sufficient Salmonella strains. We also purified AvrA and AvrA mutant proteins and characterized their deubiquitinase activity in a cell-free system. We investigated target gene and inflammatory cytokine expression, as well as effects on epithelial cell proliferation and apoptosis induced by AvrA-deficient and -sufficient bacterial strains in vivo. Our results show that AvrA blocks degradation of IkappaBalpha and beta-catenin in epithelial cells. AvrA deubiquitinates IkappaBalpha, which blocks its degradation and leads to the inhibition of NF-kappaB activation. Target genes of the NF-kappaB pathway, such as interleukin-6, were correspondingly down-regulated during bacterial infection with Salmonella expressing AvrA. AvrA also deubiquitinates and thus blocks degradation of beta-catenin. Target genes of the beta-catenin pathway, such as c-myc and cyclinD1, were correspondingly up-regulated with AvrA expression. Increased beta-catenin further negatively regulates the NF-kappaB pathway. Our findings suggest an important role for AvrA in regulating host inflammatory responses through NF-kappaB and beta-catenin pathways.
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PMID:Salmonella effector AvrA regulation of colonic epithelial cell inflammation by deubiquitination. 1769 Jan 89

Interleukin-6 (IL-6) via its signal transducer gp130 is an important mediator of liver regeneration involved in protecting from lipopolysaccharide (LPS)-induced liver injury after partial hepatectomy (PH). Here we generated mice either defective (Delta) in hepatocyte-specific gp130-dependent Ras or STAT activation to define their role during liver regeneration. Deletion of gp130-dependent signaling had major impact on acute phase gene (APG) regulation after PH. APG expression was blocked in gp130-DeltaSTAT animals, whereas gp130-DeltaRas mice showed an enhanced APG response and stronger SOCS3 regulation correlating with delayed hepatocyte proliferation. To define the role of SOCS3 during hepatocyte proliferation, primary hepatocytes were co-stimulated with IL-6 and hepatocyte growth factor. Higher SOCS3 expression in gp130-DeltaRas hepatocytes correlated with delayed hepatocyte proliferation. Next, we tested the impact of LPS, mimicking bacterial infection, on liver regeneration. LPS and PH induced SOCS3 and APG in all animal strains and delayed cell cycle progression. Additionally, IL-6/gp130-dependent STAT3 activation in hepatocytes was essential in mediating protection and thus required for maximal proliferation. Unexpectedly, oncostatin M was most strongly induced in gp130-DeltaSTAT animals after PH/LPS-induced stress and was associated with hepatocyte proliferation in this strain. In summary, gp130-dependent STAT3 activation and concomitant SOCS3 during liver regeneration is involved in timing of DNA synthesis and protects hepatocyte proliferation during stress conditions.
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PMID:Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration. 1821 23

The time course of free radical reactions is evaluated by the authors. Within pretransplant patients as of their poorly functioning metabolism free radical overproduction may be observed, hence their antioxidant capacity decreases. When the graft is functioning well, the free radical-antioxidant balance of homeostasis is reestablished. During the early postoperative period, when symptoms (acute rejection, infection, acute tubular necrosis, cholestasis) appear, free radical reactions increase. The authors demonstrate, this is strengthened by the fact that the mediator [interleukin-6 (IL-6), C-reactive protein, serum amyloid-A], and enzyme levels that take part in the free radical processes rise. The monitoring of these parameters during the early postoperative period is a good early indicator for acute rejection and for the effect of therapy. During acute rejection just as during infection most of these parameters increased significantly compared to the healthy control. They show the activation of the immune system but they are not useful for differential diagnosis, with the exception of IL-6 which we measured in larger quantities during bacterial infection but not so in acute rejection. For the prediction of early renal graft function we used urinary enzyme levels (dipeptidyl-aminopeptidase, glutathione-S-transferase). Tissue damage is followed by enzyme increasing and antioxidant capacity depletion. With choosing of adequate tests, the perioperative redox homeostasis of the transplanted patients can be monitored and with dosing the antioxidants the uncontrolled forming of reactive oxygen metabolites can also be decreased and checked.
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PMID:[Investigation of redox homeostasis in liver and renal transplant recipients]. 1834 64

During bacterial infection, the bone marrow hematopoietic activity shifts toward granulocyte production, which is critical for host defenses. Along with this enhancement of granulopoiesis, the bone marrow also increases its release of hematopoietic precursors. At the present time, little is known about the commitment of hematopoietic precursor cells, including hematopoietic stem cells and progenitors, in this response. To investigate the hematopoietic precursor cell response to bacterial infection, bacteremia was established in Balb/c mice by i.v. injection of Escherichia coli. Bacteremia caused a 10-fold increase in the number of lineage (lin)-c-kit+Sca-1+ cells in the bone marrow. This dramatic expansion of the lin-c-kit+Sca-1+ cell pool resulted from both increased mitosis of these cells and inversion from lin-c-kit+Sca-1- cell phenotype. Lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-6 were potent factors capable of mediating phenotypic inversion of lin-c-kit+Sca-1- cells. Cells in the expanded lin-c-kit+Sca-1+ cell pool contained more colony-forming unit-granulocyte/macrophage. Mobilization of lin-c-kit+Sca-1+ cells into the circulation was significantly enhanced following bacteremia. These results demonstrate that the lin-c-kit+Sca-1+ cell population in the bone marrow constitutes a key component of the host defense response to bacteremia. Functional modifications of these primitive hematopoietic precursors are critical for enhancing granulocyte production following bacterial infection.
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PMID:The lineage-c-Kit+Sca-1+ cell response to Escherichia coli bacteremia in Balb/c mice. 1848 22

Infection in neonates is difficult to identify solely on the basis of physical findings, because signs are not specific. C reactive protein (CRP) is an acute phase reactant which has been used in diagnosis of bacterial infection in neonates. IL-6 is a proinflammatory cytokine produced by monocytes and macrophages activated by bacterial infection. IL-6 can be detected in blood earlier than CRP during the course of bacterial infection. The objective of this study was to compare the usefulness of the level of interleukin-6 with CRP as early markers of neonatal sepsis. This was a queasy experimental study carried out in neonatal unit, Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU) during the period of September 2005 to February 2006. Forty five cases of suspected septicemia were enrolled in the study and thirty healthy newborns were taken for comparison. On the 1st day of symptoms and 1st day of admission, complete blood count, blood for culture and sensitivity and interleukin-6 (IL-6) estimation were done. After 48-72 hours CRP was estimated. In suspected septic babies with high leukocyte count, IL-6 level was found to be raised with high sensitivity (85.71%), negative predictive value (95%). IL-6 was found to have high sensitivity (76.9%), specificity (73.68%), positive predictive value (80%) and negative predictive value (70%) in CRP positive suspected sepsis cases. So, the conclusion was that IL-6 is a very early marker of neonatal infection. IL-6 was mostly positive within 24 hours of onset of sepsis in comparison with other tests. So IL-6 is more useful than other markers for early detection of neonatal sepsis.
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PMID:Comparison between CRP and IL-6 as early markers of neonatal sepsis. 1894 56

PCT is a 116-amino acid polypeptide glycoprotein that is ubiquitously expressed from various extrathyroid neuroendocrine tissues during bacterial infection. PCT was shown to closely correlate with the severity of sepsis. PCT synthesis is probably induced by tumor necrosis factor-alpha (TNFalpha) or interleukin-6 (IL-6), the primary cytokines in the inflammatory cascade, as they always peak before PCT. In healthy and septic animals, PCT injection did not initiate or enhance the production of TNFalpha, while TNFalpha injection induced a 25-fold massive and sustained PCT increase. This indicates that PCT release is not a ''proximal'' but rather an ''intermediary'' event in the sepsis cascade that requires a ''primed'' inflammatory background to exert its effect. PCT, a prohormone that follows a cytokine-like expression pathway, was coined a ''hormokine'' to signify its cytokine-like host-response. In our center, over a period of 2 years, we investigated subsets of postoperative ICU patients with sepsis. The area under the Receiver Operating Characteristic curve for PCT's prediction of survival outcome demonstrated a very high discriminative power of 0.90 from day 6, with a cut-off value of 3.2 ng mL(-1) PCT concentration. Interestingly, in our study, PCT declined a few days before a lethal outcome. This ominous sign clearly demonstrates that patients with poor prognosis would manifest, at a certain stage, a decrease in their ability to mount an effective response to sepsis.
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PMID:Procalcitonin's role in the sepsis cascade. Is procalcitonin a sepsis marker or mediator? 1898 69

The objective of this study was to investigate retrospectively the effect of direct hemoperfusion using polymyxin B immobilized fiber (PMX-DHP) in a cartridge to remove endotoxin on inflammatory mediators in septic patients. PMX-DHP was performed 59 times in 40 patients with severe sepsis and septic shock due to gram-negative bacterial infection. Mean age and APACHE II score were 63 years and 22, respectively. The first treatments with PMX-DHP were started when patient hemodynamics were unstable even after conventional therapies. The second treatments were performed in 19 patients whose hemodynamics were still unstable after the first PMX-DHP. The changes in inflammatory mediator levels were compared from baseline to post treatment with PMX-DHP. Statistical differences were calculated using the Wilcoxon rank sum test. Plasma endotoxin could be detected in 34 patients, which was significantly decreased in 20 cases measured by a chromogenic kinetic limulus amebocyte lysate assay (p=0.0254) and in 14 cases measured by a new limulus turbidimetric time assay (p=0.0196). Monocyte counts in peripheral blood decreased significantly (p=0.0402). Interleukin-6 decreased significantly (p=0.0020). Blood pyruvate also decreased significantly (p=0.0025). At the same time, mean arterial pressure, pulse pressure, systemic vascular resistance index, and urine output were significantly increased. These results indicated that PMX-DHP could decrease inflammatory mediators and be effective to interrupt the pathogenic sequence leading to septic shock due to gram-negative bacterial infection.
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PMID:Effect of direct hemoperfusion using polymyxin B immobilized fiber on inflammatory mediators in patients with severe sepsis and septic shock. 1900 7

Nuclear factor-kappa B (NF-kappaB) is involved in osteoclast differentiation and activation. Thus, the blockade of the NF-kappaB pathway might be a novel therapeutic strategy for treating bone metabolic diseases. Periodontitis is subgingival inflammation caused by bacterial infection; this disease also is thought to be a chronic focal point responsible for systemic diseases. In this study, NF-kappaB decoy oligodeoxynucleotides (ODNs) were topically applied for experimental periodontitis in a debris-accumulation model and wound healing in a bone-defect model of beagle dogs to investigate the effect of decoy ODN on bone metabolism. Application of NF-kappaB decoy ODN significantly reduced interleukin-6 activity in crevicular fluid and improved alveolar bone loss in the analysis of dental radiographs and DEXA. Direct measurement of exposed root that lost alveolar bone support revealed that NF-kappaB decoy treatment dramatically protected bone from loss. In a bone-defect model, NF-kappaB decoy ODN promoted the healing process as compared with control scrambled decoy in micro-CT analysis. Overall, inhibition of NF-kappaB by decoy strategy prevented the progression of bone loss in periodontitis and promoted the wound healing in bone defects through the inhibition of osteoclastic bone resorption. Targeting of NF-kappaB might be a potential therapy in various bone metabolic diseases.
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PMID:New treatment of periodontal diseases by using NF-kappaB decoy oligodeoxynucleotides via prevention of bone resorption and promotion of wound healing. 1918 92


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