Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PU.1 is a transcription factor found in macrophages, B cells, neutrophils, and hemopoietic stem cells. In macrophages PU.1 regulates a number of genes, including c-fms, CD11b, CD18, and FcgammaR1b. Previously, in primary macrophages PU.1 binding to the sequence GAGGAA was found to be induced by treatment with bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Here we investigated the role of protein kinase C (pKC) in the induction of PU.1 binding in macrophages. We report that pharmacological activation of pKC increases PU.1 binding, while inactivation of pKC inhibits the increases in PU.1 binding by agents which activate pKC in macrophages (LPS and tumor necrosis factor-alpha), but not by an agent which does not activate pKC (IFN-gamma). pKC activation may therefore be one pathway by which PU.1 binding may be increased in primary macrophages.
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PMID:Protein kinase C activation increases binding of transcription factor PU.1 in murine tissue macrophages. 992 Jul 60

Murine macrophages are able to distinguish bacterial from mammalian DNA. The response is mimicked by single-stranded oligonucleotides containing unmethylated CG dinucleotides ("CpG" motifs) in specific sequence contexts. The dose-response curve for activation is influenced by variation in the sequence flanking the core CpG motif. CpG or bacterial DNA activates several signaling pathways in common with bacterial lipopolysaccharide (LPS), leading to induction of cytokine genes such as tumor necrosis factor alpha. Pretreatment with LPS causes desensitization to subsequent activation by CpG DNA. Both stimuli also cause cell cycle arrest in macrophages proliferating in response to the macrophage growth factor colony-stimulating factor-1 (CSF-1), but prevent apoptosis caused by growth factor removal. In part, cell cycle arrest by CpG DNA and LPS may be linked to rapid down-modulation of the CSF-1 receptor from the cell surface, a response that occurs in an all-or-nothing manner. The response of macrophages to CpG DNA has aspects in common with the DNA damage response in other cell types, which may provide clues to the underlying mechanism.
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PMID:The actions of bacterial DNA on murine macrophages. 1053 6

During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.
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PMID:Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils. 1088 21

We have examined the functional antagonism between the regulator of the heat shock response, HSF1, and NF-IL6, which plays a major role in control of the acute phase response (APR). Agents that activate HSF1 such as heat shock and sodium salicylate inhibit NF-IL6 induced transcription while NF-IL6 activators such as lipopolysaccharide (LPS) and interleukin 6 (IL-6) repressed the stress responsive HSP70B promoter. In transfection studies, the inhibitory effects of HSF1 and NF-IL6 on the c-fms promoter were shown to be highly dose-dependent. Furthermore, heat shock is inhibitory to differentiation-linked expression of macrophage colony stimulating factor (M-CSF) receptor, product of the c-fms gene, which is transcriptionally activated by NF-IL6 but repressed by HSF1. Our studies suggest a strong mutual antagonism between the heat shock response and APR, which may influence the sensitivity and duration of inflammatory responses.
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PMID:NF-IL6 and HSF1 have mutually antagonistic effects on transcription in monocytic cells. 1186 74

As a c-fms-interacting protein, we cloned a novel adaptor molecule, signal-transducing adaptor protein-2 (STAP-2), which contains pleckstrin homology- and Src homology 2-like (PH and SRC) domains and a proline-rich region. STAP-2 is structurally related to STAP-1/BRDG1 (BCR downstream signaling-1), which we had cloned previously from hematopoietic stem cells. STAP-2 is a murine homologue of a recently identified adaptor molecule, BKS, a substrate of BRK tyrosine kinase. STAP-2 was tyrosine-phosphorylated and translocated to the plasma membrane in response to epidermal growth factor when overexpressed in fibroblastic cells. To define the function of STAP-2, we generated mice lacking the STAP-2 gene. STAP-2 mRNA was strongly induced in the liver in response to lipopolysaccharide and in isolated hepatocytes in response to interleukin-6. In the STAP-2(-/-) hepatocytes, the interleukin-6-induced expression of acute-phase (AP) genes and the tyrosine-phosphorylation level of STAT3 were reduced specifically at the late phase (6-24 h) of the response. These data indicate that STAP-2 plays a regulatory role in the AP response in systemic inflammation. STAP-2 contains a YXXQ motif in the C-terminal region that is a potential STAT3-binding site. Overexpression of wild-type STAP-2, but not of mutants lacking this motif, enhanced the AP response element reporter activity and an AP protein production. These data suggest that STAP-2 is a new class of adaptor molecule that modulates STAT3 activity through its YXXQ motif.
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PMID:STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif. 1254 Aug 42

The colony-stimulating factor 1 (CSF-1) receptor is a protein-tyrosine kinase that regulates cell division, differentiation, and development. In response to phorbol 12-myristate 13-acetate (PMA), the CSF-1 receptor is subject to proteolytic processing. Use of chimeric receptors indicates that the CSF-1 receptor is cleaved at least two times, once in the extracellular domain and once in the transmembrane domain. Cleavage in the extracellular domain results in ectodomain shedding while the cytoplasmic domain remains associated with the membrane. Intramembrane cleavage depends on the sequence of the transmembrane domain and results in the release of the cytoplasmic domain. This process can be blocked by gamma-secretase inhibitors. The cytoplasmic domain localizes partially to the nucleus, displays limited stability, and is degraded by the proteosome. CSF-1 receptors are continuously subject to down-modulation and regulated intramembrane proteolysis (RIP). RIP is stimulated by granulocyte-macrophage-CSF, CSF-1, interleukin-2 (IL-2), IL-4, lipopolysaccharide, and PMA and may provide the CSF-1 receptor with an additional mechanism for signal transduction.
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PMID:Phorbol 12-myristate 13-acetate-induced release of the colony-stimulating factor 1 receptor cytoplasmic domain into the cytosol involves two separate cleavage events. 1467 77

Microglia play a critical role in neurodegenerative diseases and in the brain aging process. Yet, little is known about the functional dynamics of microglia during aging. Thus, using young and aging transgenic mice expressing enhanced-green fluorescent protein (EGFP) under the promoter of the c-fms gene for macrophage-colony stimulating factor receptor, we evaluated in vivo-induced inflammatory responses of EGFP-expressing microglia sorted by flow cytometry. Aging microglia were characterized by the presence of lipofuscin granules, decreased processes complexity, altered granularity, and increased mRNA expression of both pro-inflammatory (TNFalpha, IL-1beta, IL-6) and anti-inflammatory (IL-10, TGFbeta1) cytokines. Following lipopolysaccharide (LPS) challenge (1 mg/kg, 3 h), aging microglia exhibit increased basal expression of TNFalpha, IL-1beta, IL-6, and IL-10. Yet, the fold-over-basal LPS response remained constant across age, implying that the inflammatory machinery in aging microglia is functional and adjusted to the basal state. Gender differences were not overall observed across the treatments (age, LPS). The low but sustained production of pro-inflammatory cytokines by aging microglia may have a profound impact in the brain aging process.
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PMID:Microglia derived from aging mice exhibit an altered inflammatory profile. 1720 73

The cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Proc Natl Acad Sci U S A 83:3331-3335, 1986) kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) inhibits colony-stimulating factor (CSF)-1-induced monocyte growth and bone degradation in vitro and inhibits CSF-1 signaling through cFMS kinase in 4-day models in mice (Proc Natl Acad Sci U S A 102:16078, 2005). In the present study, the kinase selectivity of GW2580 was further characterized, and the effects of chronic treatment were evaluated in normal and arthritic rats. GW2580 selectively inhibited cFMS kinase compared with 186 other kinases in vitro and completely inhibited CSF-1-induced growth of rat monocytes, with an IC(50) value of 0.2 microM. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-alpha production by 60 to 85%, indicating a duration of action of at least 5 h. In a 21-day adjuvant arthritis model, GW2580 dosed twice a day (b.i.d.) from days 0 to 21, 7 to 21, or 14 to 21 inhibited joint connective tissue and bone destruction as assessed by radiology, histology and bone mineral content measurements. In contrast, GW2580 did not affect ankle swelling in the adjuvant model nor did it affect ankle swelling in a model where local arthritis is reactivated by peptidoglycan polysaccharide polymers. GW2580 administered to normal rats for 21 days showed no effects on tissue histology and only modest changes in serum clinical chemistry and blood hematology. In conclusion, GW2580 was effective in preserving joint integrity in the adjuvant arthritis model while showing minimal effects in normal rats.
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PMID:Effects of the cFMS kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in normal and arthritic rats. 1843 89

Monocyte heterogeneity has been studied extensively in man but only recently tools have been developed to study blood monocyte populations in the mouse. We have used the MacGreen mouse model, which expresses the green fluorescent protein under the control of the promoter of the murine M-CSF receptor (CSF1 receptor, c-fms). Since both monocytes and granulocytes show GFP expression in this model the latter cells were excluded by staining with the Ly6G granulocyte marker. GFP+ Ly6G- blood monocytes were found to account for an average of 246+/-121cells/microl in these mice. These monocytes can be subdivided into CD43+ GR-1+ cells and CD43++ GR-1(-) cells, with the latter cells accounting for 140+/-77cells/mul, i.e. about 60% of all blood monocytes. After intraperitoneal injection of lipopolysaccharide (LPS) both blood monocyte subpopulations were depleted. The same was true after intranasal infection with Streptococcus pneumoniae but here the CD43++ subpopulation was preferentially reduced to 4cells/mul. For the study of TNF expression cells were stimulated in vitro with LPS from Salmonella abortus equi in the presence of Brefeldin A followed by intracellular staining and multicolor flow cytometry. Over a dose range of 10-100ng LPS/ml, TNF protein production was significantly higher in the CD43++ monocyte subset. At 1000ng LPS/ml 90% of all CD43++ monocytes stained positive for TNF and in terms of fluorescence intensity TNF was 5-fold higher compared to the CD43+ monocytes. These data indicate that the murine CD43++ monocyte subset exhibits features of pro-inflammatory monocytes and is functionally homologeous to the human CD14+CD16+ monocytes.
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PMID:Increased TNF expression in CD43++ murine blood monocytes. 1846 96

Bone marrow (BM)-FMS-like tyrosine kinase 3 (Flt3) ligand-murine dendritic cells (DC) in response to group A streptococcal (GAS) lipopeptide vaccines containing an analogue of a Toll-like receptor (TLR) 2 agonist showed significant up-regulation in expression of DC maturation markers CD40 and CD80 when compared to unstimulated controls. There were significant increases in MHC class II, CD40, CD80 and CD86 expression on classical DC and plasmacytoid DC after in vivo administration or in vitro stimulation of BM-granulocyte macrophage colony stimulating factor (GMCSF)-DC with lipopolysaccharide but not lipopeptide GAS vaccines. Our results indicate that an LCP-GAS vaccine induced phenotypic maturation of BM-Flt3-DC but not BM-GMCSF-DC.
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PMID:Expression of maturation markers on murine dendritic cells in response to group A streptococcal lipopeptide vaccines. 1920 Aug 39


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