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

We have demonstrated that CD45, a receptor-type protein tyrosine phosphatase, selectively regulates IgG production at the generative phase of precursors of IgG producers whereas Lyb-2 regulates IgG1 production induced by IL-4 in lipopolysaccharide (LPS)-activated B cells by acting on the generation of IgG1 precursor cells. These results point to an interesting possibility that both CD45 and Lyb-2 mediate a critical regulatory step(s) in IgG class switching. The present study was conducted to examine this possibility by elucidating the molecular mechanisms whereby CD45 and Lyb-2 control IgG synthesis in B cells activated by LPS and IL-4. Northern blot analysis showed that steady-state levels of C gamma 3, C gamma 2b and C gamma 1, but not Cmu, mRNA in LPS-activated B cells were reduced approximately 3- to 5-fold by CD45 mAb, and that the C gamma 1 mRNA level in B cells activated by LPS and IL-4 was significantly decreased by Lyb-2 mAb and CD45 mAb. Further, CD45 mAb inhibited expression of germline gamma 2b and gamma 3 transcripts induced by LPS and germline gamma 1 transcript expression induced by IL-4 plus LPS, but caused no inhibition in IL-4-induced germline gamma 1 transcript expression. In contrast, Lyb-2 mAb did not exert any inhibitory effect on the generation of germline gamma 1 transcripts induced by IL-4 and LPS or by IL-4 alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of lipopolysaccharide- and IL-4-induced immunoglobulin heavy chain gene activation: differential roles for CD45 and Lyb-2. 153 9

Continuous infusion of a nonlethal dose of Escherichia coli lipopolysaccharide (LPS) into rats induced extravasation of mononuclear phagocytes into the liver and the priming of Kupffer cells for in vitro phorbol myristate acetate (PMA)-stimulated superoxide anion (O2-) release. The purpose of this investigation was to determine the role of protein kinase C (PKC), protein serine-threonine phosphatase(s) 1 and 2a, protein tyrosine kinase(s) and phosphatase(s), phospholipase A2 (PLA2), arachidonic acid (AA) and its cyclooxygenase (CO) and 5-lipoxygenase (5-LO) metabolites in the modulation of PMA-stimulated O2-generation in in vivo LPS-primed rat Kupffer cells. The following inhibitors blocked PMA-stimulated O2- generation in the absence (-AA) or presence of AA (+AA) (50 microM): 1) staurosporine, a putative PKC inhibitor (150 nM, 95% inhibition without AA, 88% inhibition with AA); 2) okadaic acid, a protein serine-threonine phosphatase inhibitor (2 microM, 65% inhibition with or without AA); 3) the marine PLA2 inhibitor manoalide (1 microM, 97.5% inhibition without AA, 75% with AA). In addition, it was observed that exogenously added AA enhanced PMA-stimulated O2- generation in a time- and dose-dependent manner (5-50 microM) and partially reversed the inhibitory effect of manoalide. The following inhibitors did not block PMA-stimulated O2- generation in the absence or presence of AA: 1) indomethacin, a CO inhibitor (1-100 microM) and WY-50,295M tromethamine, a novel 5-LO inhibitor (1-100 microM); 2) genistein, a protein tyrosine kinase inhibitor (1-100 microM); and 3) sodium orthovanadate (1-300 microM), a protein tyrosine phosphatase inhibitor. It was concluded that, in in vivo LPS-primed Kupffer cells, PMA-stimulated O2- generation is modulated by PKC, protein serine-threonine phosphatase(s), PLA2 and AA but not by protein tyrosine kinase(s) and phosphatase(s) and CO and 5-LO products. These findings could have implications on the design of novel therapeutic approaches for the modulation of enhanced O2- release by Kupffer cells in endotoxemia.
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PMID:Modulation of superoxide generation in in vivo lipopolysaccharide-primed Kupffer cells by staurosporine, okadaic acid, manoalide, arachidonic acid, genistein and sodium orthovanadate. 830 64

Tyrosine phosphorylation is an important mechanism of cell regulation and has been recently implicated in defense strategies against a variety of pathogens. We have investigated the involvement of protein tyrosine kinase activity in the Leishmania attachment, invasion and survival within macrophages, as well as promastigote ability to trigger tyrosine phosphorylation, which could contribute to leishmanicidal activity. Treatment of murine macrophage monolayers with genistein, herbimycin A, tyrphostin 25 or staurosporine prior to infection decreased parasite invasion in a dose-dependent manner. Contrary, addition of sodium orthovanadate, a protein tyrosine phosphatase inhibitor, phosphotyrosine and p-nitrophenyl phosphate to the interaction medium, significantly increased parasite binding and internalization, whereas phosphoserine and phosphothreonine had no effect. The phosphatase activity of intact promastigotes was greater than that of macrophages. Western blot analysis revealed tyrosine-phosphorylated bands from 198 to 28 kDa following macrophage challenge with promastigotes. Uninfected macrophages displayed no detectable tyrosine phosphorylated proteins, possibly indicating an inducible process, while in parasites it was constitutive, as seen by the presence of 42, 40 and 35 kDa phosphoproteins on the Leishmania lysates. Immunofluorescence and immunogold detection of phosphotyrosine residues in some promastigote-macrophage attachment areas, but not in the vicinity of ingested parasites, suggest that Leishmania-induced tyrosine phosphorylation is an early, local and short-lived event. Genistein treatment of Leishmania-infected cells significantly enhanced the parasite burden. This antagonist also diminished nitric oxide production in resting and interferon gamma/lipopolysaccharide-activated infected macrophages, which may account for the increased parasite survival. We propose that protein tyrosine kinase-linked pathways regulate the Leishmania promastigote invasion and the macrophage microbicidal activity.
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PMID:Leishmania-induced tyrosine phosphorylation in the host macrophage and its implication to infection. 890 99

Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5' region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients <40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients. G-allele-containing CTLA-4 genotypes (relative risk (RR)= 1.5; 95% confidence interval (CI) = 1.2-2.0; P < 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hormone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were determined, but association between CTLA-4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA- or INS-linked risk. In conclusion, the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.
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PMID:CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry. 935 55

The spectrum of protein tyrosine phosphatases (PTPs) expressed in bone marrow-derived murine macrophages (BMMs) was examined using reverse transcriptase-polymerase chain reaction. Ten different PTP cDNAs were isolated and in this study we focus on mDEP-1, a type III receptor PTP. Three mDEP-1 transcripts were expressed in primary macrophages and macrophage cell lines and were induced during macrophage differentiation of M1 myeloid leukemia cells. A variant mRNA was identified that encodes an alternate carboxyl-terminus and 3' UTR. The expression of mDEP-1 was down-regulated by CSF-1 (macrophage colony-stimulating factor) and up-regulated by bacterial lipopolysaccharide, an important physiological regulator of macrophage function that opposes CSF-1 action. Whole mount in situ hybridization, and immunolocalization of the protein, confirmed that mDEP-1 is expressed by a subset of embryonic macrophages in the liver and mesenchyme. mDEP-1 was also detected in the eye and peripheral nervous system of the developing embryo. Attempts to express mDEP-1 constitutively in the macrophage cell line RAW264 were unsuccessful, with results suggesting that the gene product inhibits cell proliferation.
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PMID:Murine DEP-1, a receptor protein tyrosine phosphatase, is expressed in macrophages and is regulated by CSF-1 and LPS. 982 76

Signaling by lipopolysaccharide (LPS) through CD14 involves the activation of protein tyrosine kinases of the src family and leads to cytokine production and activation of arachidonic acid metabolism in macrophages. CD45 protein tyrosine phosphatase (PTPase) might play a role in modulating the response through this pathway. Although a critical role in regulation of T-cell signaling for CD45 has been demonstrated, little is known about its role in macrophages. Monoclonal antibodies to CD45 and F(ab')(2) fragments of the monoclonal antibody enhanced the response of differentiated THP-1 monocytic cells to LPS for the release of radiolabeled arachidonic acid metabolites, prostaglandin E(2), and tumor necrosis factor alpha. The enhancing effect of anti-CD45 mAbs was shown to occur primarily through CD14-dependent signaling by performing the experiments under conditions favoring that pathway. Further, LPS may be able to alter the enzymatic activity of CD45, as shown by Western blots of CD45 immunoprecipitates in which LPS caused a transient change in the phosphorylation state of CD45. We conclude that CD45 appears to play a role in LPS-induced responses through the CD14 pathway, possibly through its PTPase activity.
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PMID:Monoclonal antibodies to CD45 modify LPS-induced arachidonic acid metabolism in macrophages. 1069 60

Previous studies have shown that exogenously generated nitric oxide (NO) inhibits smooth muscle cell proliferation. In the present study, we stimulated rabbit vascular smooth muscle cells (RVSMC) with E. coli lipopolysaccharide (LPS), a known inducer of NO synthase transcription, and established a connection between endogenous NO, phosphorylation/dephosphorylation-mediated signaling pathways, and DNA synthesis. Non-confluent RVSMC were cultured with 0, 5, 10, or 100 ng/ml of the endotoxin. NO release was increased by 86.6% (maximum effect) in low-density cell cultures stimulated with 10 ng/ml LPS as compared to non-stimulated controls. Conversely, LPS (5 to 100 ng/ml) did not lead to enhanced NO production in multilayered (high density) RVSMC. DNA synthesis measured by thymidine incorporation showed that LPS was mitogenic only to non-confluent RVSMC; furthermore, the effect was prevented statistically by aminoguanidine (AG), a potent inhibitor of the inducible NO synthase, and oxyhemoglobin, an NO scavenger. Finally, there was a cell density-dependent LPS effect on protein tyrosine phosphatase (PTP) and ERK1/ERK2 mitogen-activated protein (MAP) kinase activities. Short-term transient stimulation of ERK1/ERK2 MAP kinases was maximal at 12 min in non-confluent RVSMC and was prevented by preincubation with AG, whereas PTP activities were inhibited in these cells after 24-h LPS stimulation. Conversely, no significant LPS-mediated changes in kinase or phosphatase activities were observed in high-density cells. LPS-induced NO generation by RVSMC may switch on a cell density-dependent proliferative signaling cascade, which involves the participation of PTP and the ERK1/ERK2 MAP kinases.
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PMID:Effects of lipopolysaccharide on low- and high-density cultured rabbit vascular smooth muscle cells: differential modulation of nitric oxide release, ERK1/ERK2 MAP kinase activity, protein tyrosine phosphatase activity, and DNA synthesis. 1184 21

Osteoclasts are hemopoietic cells that participate in bone resorption and remodeling. Receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are critical for development of osteoclasts. The Toll-like receptor (TLR) family shares some of the downstream signaling with RANK. The TLR4 ligand, lipopolysaccharide (LPS), is reported to accelerate bone lysis; however, signaling via TLRs has never been reported to induce osteoclastogenesis without RANKL. In this study we showed that significant numbers of mature osteoclasts were generated from protein tyrosine phosphatase Src homology 2-domain phosphatase-1-defective Hcph(me-v)/Hcph(me-v) (me(v)/me(v)) bone marrow cells in the presence of M-CSF and LPS without addition of RANKL in culture. This M-CSF plus LPS-induced osteoclastogenesis was not inhibited by an anti-TNFalpha antagonistic antibody or by osteoprotegerin, a decoy receptor for RANKL. The replacement of RANKL by TLR ligands only occurred with LPS. Other ligands, a peptidoglycan for TLR2 or an unmethylated CpG oligonucleotide for TLR9, did not support osteoclast generation. The osteoclast precursors as well as RANKL-responsive osteoclast precursors were present in the Kit-positive cell-enriched fraction of bone marrow cells. Although me(v)/me(v) bone marrow cells required a comparable concentration of RANKL or TNFalpha as wild-type cells for the initiation of osteoclastogenesis, the numbers of multinucleated osteoclasts in me(v)/me(v) bone marrow cultures were significantly increased by the equivalent dose of RANKL or TNFalpha in the presence of M-CSF. These results indicate that a defect of Src homology 2-domain phosphatase-1 function not only accelerates physiological osteoclast development by RANKL/RANK, but also acquires a novel pathway for osteoclastogenesis by LPS.
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PMID:Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice. 1498 81

IL (interleukin)-6 exerts pro- as well as anti-inflammatory activities. Beside many other activities, IL-6 is the major inducer of acute phase proteins in the liver, acts as a differentiation factor for blood cells, as migration factor for T-cells and is a potent inducer of the chemokine MCP-1 (monocyte chemoattractant protein-1). Recent studies have focused on the negative regulation of IL-6 signal transduction through the IL-6-induced feedback inhibitors SOCS (suppressor of cytokine signalling) 1 and SOCS3 or the protein tyrosine phosphatases SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) and TcPTP (T-cell protein tyrosine phosphatase). Studies on the cross-talk between pro-inflammatory mediators (IL-1, tumour necrosis factor, lipopolysaccharide) and IL-6 elucidated further regulatory mechanisms. Less is known about the regulation of IL-6 signal transduction by hormone/cytokine signalling through G-protein-coupled receptors. This is particularly surprising since many of these hormones (such as prostaglandins and chemokines) play an important role in inflammatory processes. In the present study, we have investigated the inhibitory activity of PGE(1) (prostaglandin E(1)) on IL-6-induced MCP-1 expression and have elucidated the underlying molecular mechanism. Surprisingly, PGE(1) does not affect IL-6-induced STAT (signal transducer and activator of transcription) 3 activation, but does affect ERK (extracellular-signal-regulated kinase) 1/2 activation which is crucial for IL-6-dependent expression of MCP-1. In summary, we have discovered a specific cross-talk between the adenylate cyclase cascade and the IL-6-induced MAPK (mitogen-activated protein kinase) cascade and have investigated its impact on IL-6-dependent gene expression.
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PMID:Prostaglandin E1 inhibits IL-6-induced MCP-1 expression by interfering specifically in IL-6-dependent ERK1/2, but not STAT3, activation. 1827 57

SHP-1 is a cytoplasm protein tyrosine phosphatase expressed primarily in hematopoietic cells. In the immune system, SHP-1 plays critical roles in regulation of many receptor-mediated signaling cascades, and SHP-1 deficiency in mice causes spontaneous inflammation and autoimmunity. Here, we report a unique requirement for SHP-1 in interleukin-12/23 p40 (IL-12p40) production in response to Toll-like receptor (TLR) stimulation in macrophages. Bone marrow-derived macrophages (BMDMs) lacking significant SHP-1 activity display a profound defect in IL-12p40 synthesis in response to lipopolysaccharide, peptidoglycan, and synthetic TLR ligands, while producing normal amounts of other proinflammatory cytokines, such as TNFalpha and IL-6. Inhibition of SHP-1 function in wild-type BMDMs decreases IL-12p40, and expression of functional SHP-1 protein in mutant cells restores IL-12p40 production following TLR ligation. SHP-1 regulation of IL-12p40 transcription requires both its catalytic activity and phosphotyrosine binding by its N-terminal SH2 domain and is mediated via repression of, and interaction with, phosphatidylinositol 3-kinase, without affecting c-Rel activation. In contrast to normal NF-kappaB activation, SHP-1-defective me(v)/me(v) macrophages display a defect in nucleosome remodeling at the IL-12p40 promoter, and phosphatidylinositol 3-kinase inhibition significantly restores normal nucleosome remodeling in me(v)/me(v) macrophages. Thus, there is a critical role for the tyrosine phosphatase activity of SHP-1 for induction of IL-12p40 production in macrophages in response to TLR ligands, a novel mechanism for host regulation of a specific proinflammatory cytokine important in both innate and adaptive immunity.
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PMID:Protein tyrosine phosphatase SHP-1 positively regulates TLR-induced IL-12p40 production in macrophages through inhibition of phosphatidylinositol 3-kinase. 2014


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