Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater beta-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon gamma (INF-gamma, 5000 units). LPS/INF-gamma depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. beta-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-gamma hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950+/-160 fmol/min/g) v young (2440+/-170 fmol/min/g, P=0.05) LPS/INF-gamma hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed beta-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-gamma was approximately 2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-gamma. These findings indicate that advanced age is associated with augmented cardiac beta-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.
J Mol Cell Cardiol 2001 Oct
PMID:Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma. 1160 26

Pneumocystis carinii is fungus which is a frequent cause of severe pneumonia in immunocompromised individuals. The P. carinii genome contains the PRT1 subtelomeric multigene family that encodes a kexin-like serine protease which is expressed on the surface of P. carinii. Analysis of the sequence of the carboxy-terminal sequence of many copies of PRT1 showed that they contained motifs characteristic of a glycosylphosphatidylinositol (GPI) anchor signal sequence. The ability of the C-terminal sequences of PRT1 to direct the addition of a GPI anchor was tested. CD14, a GPI-anchored monocyte glycoprotein antigen, was used as the basis of a heterologous system. CD14 was truncated to remove the carboxy-terminal sequences responsible for GPI-anchor addition. Addition of carboxy-terminal sequences from PRT1 restored high-level surface expression to the truncated CD14. Further, the majority of CD14-PRT1 recombinant protein was removed from the cell membrane by treatment with GPI-specific phospholipase C. These results suggest that the carboxy-terminal residues of most of the members of the PRT1 family of proteases have the potential to form a functional GPI-attachment signal.
Am J Respir Cell Mol Biol 2001 Oct
PMID:Functional glycosylphosphatidylinositol anchor signal sequences in the Pneumocystis carinii PRT1 protease family. 1169 52

Decidual stromal cells (DSC) are the main cellular component of the human decidua, but thus far their ascription to a given cell lineage is uncertain. In previous studies, these cells have been isolated and maintained in culture, and their antigen phenotype has been analysed to determine their affiliation. However, the presence in the culture medium of high proportions of fetal calf serum (FCS) may inhibit the expression of some surface antigens. In the present study, we show by flow cytometry that CD34 is rapidly down-regulated in human DSC cultured in RPMI 1640 with 20% FCS. For this reason, we used fibroblast medium, which contains only a small proportion (2%) of FCS, to isolate and culture these cells. Under these conditions DSC exhibited a stable antigen phenotype highly similar to that of these cells in vivo. Flow cytometry results confirmed that DSC cultured in fibroblast medium expressed CD34 protein, and reverse transcription-polymerase chain reaction findings showed that they have CD34 mRNA. Decidual stromal cells were also positive for STRO-1, an antigen that identifies stromal precursors of the bone marrow which also expresses CD34. The expression of CD10, CD13, alkaline phosphatase and alpha-smooth muscle actin by DSC, and the absence of expression of CD14 and CD45, further confirmed their relationship with the stromal precursors.
Mol Hum Reprod 2001 Dec
PMID:Human decidual stromal cells express CD34 and STRO-1 and are related to bone marrow stromal precursors. 1171 92

Kupffer cells are involved in the pathogenesis of chemically mediated liver injury through release of biologically active mediators that promote the pathogenic process. The purpose of this study was to elucidate specific biochemical and molecular changes occurring in Kupffer cells throughout a time course of carbon tetrachloride (CCl(4))-mediated liver injury and fibrosis. Rats were administered 1 ml/kg of CCl(4) (10% v/v olive oil) twice weekly for up to 6 weeks. Plasma alanine aminotransferase values and hematoxylin-and-eosin- and trichrome-stained liver sections indicated minor liver damage at 2 weeks followed by increased damage and collagen deposition by 4 and 6 weeks. Additionally, mRNA levels in Kupffer cells isolated from CCl(4)-treated rats demonstrated significant increases in tumor necrosis factor alpha (TNF alpha); tumor growth factor beta; interleukin-6 (IL-6); interleukin 1 beta; cyclooxygenase 2; CD14, and I kappa B alpha transcripts after 2 and 4 weeks of treatment. However, the expression of these genes at 6 weeks was similar to that of controls. Increased gene expression of cytokines in Kupffer cells isolated from CCl(4)-treated rats was accompanied by increases in protein production of TNF alpha, IL-6, IL-1 beta, and interleukin 10 following lipopolysaccharide stimulation. Further, liver sections stained for ED2-positive cells demonstrated an increase in the number of resident macrophages at 2 and 4 weeks with a slight decrease in ED2-positive cells by week 6 but still significantly more than control. Analysis of reduced glutathione (GSH) and oxidized glutathione (GSSG) indicated that Kupffer cells from CCl(4)-treated animals exhibited a 50% decrease in GSH at 2 and 4 weeks, whereas no significant changes were observed for GSSG. In conclusion, these data implicate Kupffer cells as a critical mediator of the inflammatory and fibrogenic responses during CCl(4)-mediated liver damage and provide new insight into the temporal molecular and biochemical changes associated with the ability of these resident macrophages to modulate liver injury.
Exp Mol Pathol 2001 Dec
PMID:Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. 1173 48

Although the potent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been well known for its immunosuppressive activity, the mechanisms of its action have been difficult to elucidate. This is partly due to its inability to exert its effects in vitro. To further elucidate the underlying mechanisms of TCDD effects, we screened for genes that are regulated by the in vivo TCDD treatment of mice that are challenged with allogeneic tumor cells. RNA, collected from lymphoid organs including the thymus, draining lymph nodes, and bone marrow, was reverse-transcribed to cDNA and hybridized to DNA arrays that consisted of 588 genes (ClonTech, USA). The expression of the NF-kappaB p65, c-jun, and p27(Kip1) genes was increased by the TCDD treatment, as previously reported. In addition, we found that the expression of several genes, which were not reported as regulated by TCDD, were modulated by TCDD. Some genes, including insulin-like growth factor-binding protein-6 (IGFBP-6) and IL-5R alpha, were upregulated; while other genes, including CD14, were down-regulated. The expression of the IGFBP-6 and IL-5R alpha subunit genes by TCDD in the thymus was confirmed by RT-PCR and Western blot analyses. Furthermore, TCDD effects on the expression of the IGFBP-6 gene was also observed with EL4 mouse thymoma cells. This suggests that IGFBP-6 may be involved in thymic atrophy, and EL4 cells may be used as an in vitro model for studying molecular mechanisms of thymic atrophy.
Mol Cells 2001 Dec 31
PMID:TCDD-up-regulation of IGFBP-6 and IL-5R alpha subunit genes in vivo and in vitro. 1180 38

The c-fps/fes proto-oncogene encodes a 92-kDa protein tyrosine kinase that is preferentially expressed in myeloid and endothelial cells. Fes is believed to play a role in vascular development and myelopoiesis and in the inflammatory responses of granulocytes and macrophages. To help define the biological role of this kinase and identify its downstream targets, we have developed a gain-of-function allele of Fes that has potent biological activity in myeloid cell progenitors. Introduction of constitutively active Fes into bipotential U937 cells induced the appearance of fully differentiated macrophages within 6 to 12 days. The Fes-expressing differentiated cells became adherent, had distinctive macrophage morphology, and exhibited increased expression of myelomonocytic differentiation markers, including CD11b, CD11c, CD18, CD14, and the macrophage colony-stimulating factor receptor. These cells acquired phagocytic properties and exhibited NADPH oxidase and nonspecific esterase activities, confirming that they were functionally active macrophages. Concomitantly, there was downregulation of the granulocytic marker granulocyte colony-stimulating factor receptor, indicating that the biological activity of Fes was coordinated in a lineage-specific manner. A constitutively active Src did not induce macrophage morphology or upregulation of myelomonocytic markers in U937 cells, suggesting that the biological activity we observed was not a general consequence of expression of an activated nonreceptor tyrosine kinase. Analysis of possible downstream targets of Fes revealed that this kinase activated the ets family transcription factor PU.1, which is essential for macrophage development. Our results strongly implicate Fes as a key regulator of terminal macrophage differentiation and identify PU.1 as a transcription factor that may mediate some of its biological activities in myeloid cells.
Mol Cell Biol 2002 Mar
PMID:Activated Fes protein tyrosine kinase induces terminal macrophage differentiation of myeloid progenitors (U937 cells) and activation of the transcription factor PU.1. 1186 67

Vitamin E-succinate (VES) induced monocvtic differentiation of HL-60 human leukemia cells. Treatment with VES increased the nitroblue tetrazolium reduction activity, and the expression of monocyte specific cell surface antigen, CD14 and c-fms. During the monocytic differentiation of HL-60 cells that were induced by VES, the phosphorylation of extracellular signal-regulated protein kinase (ERK) was increased by 12 h and then gradually decreased to a level that was similar to that of the control. However, the phosphorylation levels of p38 and JNK, as well as the expression levels of ERK, p38, and JNK, were unchanged by the VES treatment. Treatment with VES also induced hypophosphorylation of the retinoblastoma protein and an increase of the p21WAF1 protein level. VES-induced ERK phosphorylation was abolished by the ERK inhibitor, PD98059, which resulted in a remarkable prevention of VES-induced monocytic differentiation. Inhibition of the ERK activity by PD98059 also diminished the VES-induced p21WAF1 protein expression, but did not change the phosphorylation state of the retinoblastoma protein. Collectively, these data suggest that the ERK signaling pathway mediates the up-regulation of the p21xWAF1 expression that is induced by VES, which is required for monocytic differentiation of HL 60 cells.
Mol Cells 2002 Feb 28
PMID:Expression of p21WAF1 is dependent on the activation of ERK during vitamin E-succinate-induced monocytic differentiation. 1191 63

The triggering receptor expressed on myeloid cells (TREM-1) and the myeloid DAP12-associating lectin (MDL-1) are two recently identified receptors which associate non-covalently with DAP12 to form receptor complexes involved in monocytic activation and inflammatory response. In this study, we investigated whether the expression of TREM-1, MDL-1, and DAP12 correlated with myelomonocytic differentiation. Northern and RT-PCR revealed a strong expression of TREM-1, MDL-1, and DAP12 in peripheral blood-derived CD14(+) mature monocytes in contrast to undifferentiated bone marrow CD34(+) stem cells, and in the differentiated versus undifferentiated U937 cells. TREM-1 and MDL-1 RNA expression was also more elevated in adult than fetal tissues and in normal than malignant cells. These findings suggest that the TREM-1/DAP12 and MDL-1/DAP12 signaling pathways are features of mature differentiated myelomonocytic cells. In addition, expression of an alternative mRNA TREM-1 splice variant (TREM-1sv) was detected that might translate into a soluble receptor with potential as a regulator of myeloid activation.
Mol Immunol 2002 Mar
PMID:TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of myeloid development. 1192 39

Lipopolysaccharide (LPS) has a profound effect on cardiac performance through a collapse of the vasculature. In this study, we determined whether LPS has a direct effect on the cardiac myocytes by examining the expression of the BNP gene in cultured neonatal rat cardiac myocytes. Northern blot analysis showed that LPS induces the expression of the BNP gene. Time-course experiments revealed that BNP mRNA levels were increased 1 h after LPS stimulation. Enhanced induction of BNP was observed 3 h after stimulation when expression of CD14, a specific receptor for LPS, was markedly induced. LPS-mediated BNP expression was completely inhibited by the pretreatment of SB203580, a specific inhibitor for p38 MAPK as well as by genistein, a broad range tyrosine kinase inhibitor. In accordance with these results, LPS increases phosphorylation of p38 mitogen-activated protein kinase (MAPK). Transient transfection assays revealed that low dose (1 ng/ml) of LPS induces the luciferase activity derived from the construct containing the BNP promoter spanning from -1000 and +80 in front of the luciferase gene. Cotransfection of the expression vectors for constitutive active forms of Rac1, MKK3 and p38 MAPK significantly increased BNP promoter activity. Mutation of the GATA sequence located at -95 and -84 abolished such an induction of BNP promoter activity. Overexpression of CD14 enhanced the LPS's effect on BNP promoter. These results indicate that LPS induces the BNP gene expression through a pathway involving CD14, Rac1, p38 MAPK and GATA elements. In addition to the induction of BNP expression by hemodynamic overload, our data suggest that elevated levels of BNP under the endotoxemic condition is partly mediated through the increased expression of CD14, which lies upstream of the Rac1-p38 MAPK pathway.
J Mol Cell Cardiol 2002 Jun
PMID:Transcriptional activation of the BNP gene by lipopolysaccharide is mediated through GATA elements in neonatal rat cardiac myocytes. 1205 52

The influence of extracellular matrix (ECM) on monocyte-macrophage (mo-mphi) differentiation was investigated using an in vitro model with human peripheral blood mononuclear cells (PBMC) maintained on different matrix protein substrata. Macrophage specific markers associated with differentiation studied were, (a) endocytosis of modified proteins; (b) appearance of mphi specific matrix metalloproteinases (MMPs); (c) activities of myeloperoxidase (MPO) and beta-D-glucuronidase; (d) changes in the expression of cell surface antigens. As the duration of monocytes in culture increased, a progressive increase in the rate of differentiation was seen as evidenced by mphi specific functions such as endocytosis of 125[I] acetyl BSA and the appearance of gelatinases A and B. Significantly higher rate of endocytosis and production of MMPs were found in monocytes maintained on fibronectin (FN) and COL I than on COL IV (FN > COL I > COL IV) indicating that cells in contact with stromal components differentiate at a faster rate. FACS analysis done on cells maintained in vitro for phenotypic profile characteristic to mo-mphi differentiation showed downregulation of CD14 occurring in a substratum dependent manner viz, (FN > COL IV > COL I) and upregulation of CD71 was high in cells maintained on COL I and COL IV. Intracellular enzymatic activities such as MPO significantly decreased irrespective of matrix substrata, while beta-D-glucuronidase activity increased in a substratum dependent manner (FN > COL I > COL IV). Pretreatment of cells with genistein significantly decreased the secretion of MMPs, particularly MMP 9 in cells maintained on ECM protein (FN) indicating a phosphorylation dependent signalling process in mediating matrix effect. The results of these in vitro studies on mphi specific markers suggest that apart from the diffusible factors, the microenvironment as provided by various matrix proteins particularly FN can modulate mo-mphi differentiation.
Mol Cell Biochem 2002 Apr
PMID:Monocyte-macrophage differentiation in vitro: modulation by extracellular matrix protein substratum. 1208 84


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