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

One of the most important issues in stem cell research is to understand the regulatory mechanisms responsible for their differentiation. An extensive understanding of mechanism underlying the process of differentiation is crucial in order to prompt stem cells to perform a particular function after differentiation. To elucidate the molecular mechanisms responsible for the hematopoietic differentiation of embryonic stem cells (ESCs), we investigated murine ES cells for the presence of hematopoietic lineage markers as well as Wnt signaling pathway during treatments with different cytokines alone or in combination with another. Here we report that Wnt/beta-catenin signaling is down-regulated in hematopoietic differentiation of murine ES cells. We also found that differentiation induced by the interleukin-3, interleukin-6, and erythropoietin combinations resulted in high expression of CD3e, CD11b, CD45R/B220, Ly-6G, and TER-119 in differentiated ES cells. A high expression of beta-catenin was observed in two undifferentiated ES cell lines. Gene and protein expression analysis revealed that the members downstream of Wnt in this signaling pathway including beta-catenin, GSK-3beta, Axin, and TCF4 were significantly down-regulated as ES cells differentiated into hematopoietic progenitors. Our results show that the Wnt/beta-catenin signaling pathway plays a role in the hematopoietic differentiation of murine ESCs and also may support beta-catenin as a crucial factor in the maintenance of ES cells in their undifferentiated state.
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PMID:A regulatory role of Wnt signaling pathway in the hematopoietic differentiation of murine embryonic stem cells. 1550 60

Plasmacytoid dendritic cells (pDCs) competent to make type I interferon were rigorously defined as a Ly-6C(+) and CD11c(Lo) subset of the B220(+)CD19(-) CD43(+)CD24(Lo) bone marrow (BM) Fraction A. Otherwise similar Ly6C(-) cells expressed the natural killer (NK) markers DX5 and NK1.1. pDCs represented a stable, discrete, and long-lived population. Stem cells and early lymphoid progenitors (ELPs), but not prolymphocytes, were effective precursors of pDCs, and their differentiation was blocked by ligation of Notch receptors. Furthermore, pDCs were present in the BM of RAG1(-/-), CD127/IL-7Ra(-/-), and Pax5(-/-) mice. pDCs in RAG1/GFP knock-in mice could be subdivided, and immunoglobulin D(H)-J(H) rearrangements, as well as transcripts for the B-lineage-related genes Pax5, mb1/CD79a, ebf, and Bcl11a, were identified only in the green fluorescent protein-positive (GFP(+)) pDC1 subset. All pDCs expressed terminal deoxynucleotidyl transferase (TdT), the ETS transcription factor Spi-B, the nuclear factor-kappaB transcription factor RelB, toll-like receptor 9 (TLR9), and interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF-8) transcripts; lacked CD16 and granulocyte colony-stimulating factor receptor (G-CSFR); and were uniformly interleukin-7 receptor alpha (IL-7Ralpha(-)) AA4.1(Lo), CD27(-), Flk-2(Lo), c-Kit(-), DX-5(-), and CD11b(-), while CD4 and CD8alpha were variable. GFP(+) pDC1 subset was less potent than GFP(-) pDC2s in T allostimulation and production of tumor necrosis factor alpha (TNFalpha), interferon alpha (IFNalpha), and interleukin-6 (IL-6), while only pDC2s made IFNgamma and IL-12 p70. Thus, 2 functionally specialized subsets of pDCs arise in bone marrow from progenitors that diverge from B, T, and NK lineages at an early stage.
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PMID:Derivation of 2 categories of plasmacytoid dendritic cells in murine bone marrow. 1572 31

Acute lung injury (ALI) induced by lipopolysaccharide (LPS) is a major cause of mortality among humans. ALI is characterized by microvascular protein leakage, neutrophil influx, and expression of proinflammatory mediators, followed by severe lung damage. LPS binding to its receptors is the crucial step in the causation of these multistep events. LPS binding and signaling involves CD14 and Toll-like receptor 4 (TLR4). However, the relative contributions of CD14 and TLR4 in the induction of ALI and their therapeutic potentials are not clear in vivo. Therefore, the aim of the present study was to compare the roles of CD14 and TLR4 in LPS-induced ALI to determine which of these molecules is the more critical target for attenuating ALI in a mouse model. Our results show that CD14 and TLR4 are necessary for low-dose (300-microg/ml) LPS-induced microvascular leakage, NF-kappaB activation, neutrophil influx, cytokine and chemokine (KC, macrophage inflammatory protein 2, tumor necrosis factor alpha, interleukin-6) expression, and subsequent lung damage. On the other hand, when a 10-fold-higher dose of LPS (3 mg/ml) was used, these responses were only partially dependent on CD14 and they were totally dependent on TLR4. The CD14-independent LPS response was dependent on CD11b. A TLR4 blocking antibody abolished microvascular leakage, neutrophil accumulation, cytokine responses, and lung pathology with a low dose of LPS but only attenuated the responses with a high dose of LPS. These data are the first to demonstrate that LPS-induced CD14-dependent and -independent (CD11b-dependent) signaling pathways in the lung are entirely dependent on TLR4 and that blocking TLR4 might be beneficial in lung diseases caused by LPS from gram-negative pathogens.
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PMID:Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury. 1573 Oct 76

Diagnosis of early-onset neonatal infection has led to the development of several screening tests including C-reactive protein, a very commonly used marker, and cytokines (mainly interleukin-6 and -8), alone or in combination with C-reactive protein, based on the premise that their increases in response to infection may precede that of C-reactive protein. In recent years the search for diagnostic tests has turned to procalcitonin, a propeptide of calcitonin, which appears to be a promising marker of infection in newborn infants. Additionally, specific leukocyte cell surface antigens (mainly CD11b and CD64), detected by flow cytometry, are evaluated as markers of neonatal infection, since their expression on the cell membrane increases in substantial quantities after leukocyte activation by bacteria or their cellular products. This review aims to examine the role of these newly available immunologic indices and to assess their validity as diagnostic markers of infection during the neonatal period.
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PMID:Immunologic markers in the neonatal period: diagnostic value and accuracy in infection. 1583 52

Stretch injury to the myotendinous junction is a common problem in competitive athletes and those involved in regular physical activity. The major risk factor for recurrent injury appears to be the primary injury itself. Physicians, physical therapists, athletic trainers and athletes alike continue to search for optimal treatment and prevention strategies. Acute inflammation is regarded as the body's generalized protective response to tissue injury. An especially important and unexplored aspect of inflammation following injury is the role of inflammatory cells in extending injury and possibly directing muscle repair. It has been suggested that the inflammatory reaction, although it typically represents a reaction to damage and necrosis, may even bring about some local damage of its own and therefore increase the possibility for scarring and fibrosis. Limiting certain aspects of inflammation may theoretically reduce muscle damage as well as signals for muscle scarring. Here we focus on the role of neutrophils in injury and repair of stretch-injured skeletal muscle. A minimally invasive model that generates a reproducible injury to rabbit skeletal muscle is presented. We present a plausible theory that neutrophil-derived oxidants resulting from the initial stretch injury are responsible for extending the damage. An anti-CD11b antibody that blocks the neutrophil's respiratory burst is employed to reduce myofibre damage. An intriguing area that is currently being explored in our laboratory and others is the potential role for neutrophils to contribute to muscle growth and repair. It may be possible that neutrophils facilitate muscle repair through removal of tissue debris as well as by activation of satellite cells. Recent and ongoing investigations point to interleukin-6 as a possible key cytokine in muscle inflammation and repair. Studies to elucidate a clearer understanding of this possibility will be reviewed.
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PMID:The role of neutrophils in injury and repair following muscle stretch. 1663 72

Traumatic brain injury causes progressive tissue atrophy and consequent neurological dysfunction, resulting from neuronal cell death in both animal models and patients. Fas (CD95) and Fas ligand (FasL/CD95L) are important mediators of apoptosis. However, little is known about the relationship between Fas and FasL and neuronal cell death in mice lacking the genes for inflammatory cytokines. In the present study, double tumor necrosis factor/lymphotoxin-alpha knockout (-/-) and interleukin-6-/- mice were subjected to closed head injury (CHI) and sacrificed at 24 hours or 7 days post-injury. Consecutive brain sections were evaluated for Fas and FasL expression, in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling; TUNEL), morphologic characteristics of apoptotic cell death and leukocyte infiltration. A peak incidence of TUNEL positive cells was found in the injured cortex at 24 hours which remained slightly elevated at 7 days and coincided with maximum Fas expression. FasL was only moderately increased at 24 hours and showed maximum expression at 7 days. A few TUNEL positive cells were also found in the ipsilateral hippocampus at 24 hours. Apoptotic, TUNEL positive cells mostly co-localized with neurons and Fas and FasL immunoreactivity. The amount of accumulated polymorphonuclear leukocytes and CD11b positive cells was maximal in the injured hemispheres at 24 hours. We show strong evidence that Fas and FasL might be involved in neuronal apoptosis after CHI. Furthermore, Fas and FasL upregulation seems to be independent of neuroinflammation since no differences were found between cytokine-/- and wild-type mice.
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PMID:Immunohistochemical characterization of Fas (CD95) and Fas Ligand (FasL/CD95L) expression in the injured brain: relationship with neuronal cell death and inflammatory mediators. 1716 98

Reparixin antagonizes interleukin-8 (IL-8) on the level of signal transduction in vitro. We hypothesized that IL-8 mediates some of the reactions occurring during acute inflammation and specifically that IL-8 may be a mediator of endotoxin induced neutrophilia. We therefore tested the effects of reparixin on humoral and cellular parameters in LPS-induced acute systemic inflammation. The study is a randomized (3:2 active:placebo), double-blind, placebo-controlled parallel group trial. Twenty healthy male volunteers randomly received either reparixin (12) or placebo (8) intravenously. One hour after the start of reparixin/placebo infusion a bolus of 2 ng/kg endotoxin was infused over 1-2 min. Blood samples were obtained over 24 h. Reparixin, being metabolized to ibuprofen, suppressed serum thromboxane B2 levels by 78 percent compared to baseline and control at 8 h. LPS-induced neutrophilia was not significantly affected by reparixin in human volunteers. Consistently, reparixin did not alter the lymphocyte or monocyte counts and had no effect on LPS-induced systemic inflammation as measured by tumor necrosis factor alpha (TNF-alpha) or interleukin-6 (IL-6) release. Regulation of IL-8 receptors CXCR1 and 2 and the degranulation marker CD11b showed the expected kinetics. Reparixin had no effect on thrombin formation as measured by prothrombin fragment (F1+2). In conclusion, our study showed that reparixin was safe but had no impact on endotoxin induced inflammation. In contrast to previous studies with its metabolite ibuprofen, reparixin does not enhance inflammation in this model.
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PMID:Reparixin, a specific interleukin-8 inhibitor, has no effects on inflammation during endotoxemia. 1734 25

Dendritic cells (DCs) polarize naive CD4(+) T cells to either T helper 1 (Th1) or Th2 cells. We examined the role of glycogen synthase kinase 3 (GSK3) activity during DC development from murine bone marrow (BM) cells. DCs were generated by culturing lineage-marker-negative BM cells with granulocyte-macrophage colony-stimulating factor in the presence or absence of a specific inhibitor of GSK3 (Gi), SB415286, for 6 days. DCs generated in the presence (GiDC) or absence (control DC) of SB415286 similarly exhibited a conventional DC phenotype (CD11b(+) B220(-) CD8(-)). These DCs were mixed with allogeneic CD4(+) T cells and the ability to polarize Th1 or Th2 cells was evaluated. The GiDCs exhibited markedly impaired function to induce Th2 polarization compared to control DCs. In contrast, the ability of GiDCs to generate Th1 cells was slightly higher than that of control DCs. CD86 expression and CD40-mediated interleukin-6 production were completely diminished in GiDCs, which might be associated with the impaired ability of the GiDCs to induce Th2 differentiation. These results suggest that the GSK3 activity during DC development is essential for the establishment of the DC function to induce Th2, but not Th1, differentiation.
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PMID:Glycogen synthase kinase 3 activity during development of bone marrow-derived dendritic cells (DCs) essential for the DC function to induce T helper 2 polarization. 1749 Apr 35

In vitro culture of rodent microglia is a common system used to model proinflammatory changes in the brain. However, typical postnatal brain isolation protocols are time consuming and cell numbers acquired are often a rate-limiting factor for experimental progress. Large studies that rely on the use of primary microglia can, therefore, require excessive numbers of animals at considerable expense, additional technical support and culture incubator space. Although the addition of mitogens such as macrophage colony-stimulating factor, granulocyte macrophage-colony stimulating factor, and epidermal growth factor to the cultures can facilitate a higher yield, this adds additional expense and likely alters the microglial phenotype. We have defined a simple, inexpensive modification of our standard culture protocol that allows us to repetitively isolate microglia. In order to define a method for improving microglia yield, we utilized our standard mixed glial culture preparation derived from postnatal day 1-3 mouse brains. After isolating microglia from mixed cultures at 14 days in vitro, we added fresh media to the cultures for an additional 7 and 14 days to monitor microglial proliferation. We acquired a constant number of cells at each successive time point although the numbers were reduced from the first isolation. More importantly, in order to determine if our successive microglia isolates differed phenotypically we characterized several parameters of function. We compared their ability to secrete the proinflammatory cytokines interleukin-6 and tumor necrosis factor alpha after LPS stimulation. We also contrasted the phagocytic ability, morphology, and specific immunoreactivity (CD11b, CD68, CD45 and MHC II) of the culture ages. Our data demonstrate that microglia can be obtained from extended-time cultures provided periodic isolation is performed. Moreover, the cells retain a comparable in vitro phenotype. This demonstrates that cells from all ages can be combined for any given study. These findings are a viable and inexpensive way to increase and extend the microglial yield without increasing the number of animals used or adding costly mitogens. This method will be particularly useful for the preparation of microglia cultures from limited transgenic colonies.
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PMID:Microglia repetitively isolated from in vitro mixed glial cultures retain their initial phenotype. 1755 68

The inflammatory response during elective open infrarenal abdominal aortic aneurysm repair and its impact on outcome is investigated. Twenty high-risk patients were enrolled, and blood samples were obtained at 8 perioperative time points. Endotoxin, cytokines (tumor necrosis factor-alpha and interleukin-1beta, and interleukin-6), CD11b expression, and nitric oxide were measured. Peak endotoxin levels occurred within 30 minutes of reperfusion and were higher among patients developing complications. Interleukin-6 levels increased during reperfusion, reaching a peak on the first postoperative day. Interleukin-6 increase correlated with aortic clamp time and morbidity. CD11b expression increased 30 minutes after reperfusion, and this effect was greater among patients who developed complications. Endotoxin may be important in the pathogenesis of multiple organ dysfunction syndrome. Activated neutrophils may have a central role in tissue injury after reperfusion. Intraoperative CD11b upregulation may be an early marker for postoperative complications after infrarenal abdominal aortic aneurysm repair.
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PMID:A global assessment of the inflammatory response elicited upon open abdominal aortic aneurysm repair. 1823 67


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