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)

Depending on sequence, bacterial and synthetic DNAs can activate the host immune system and influence the host response to infection. The purpose of this study was to determine the abilities of various phosphorothioate oligonucleotides with cytosine-guanosine-containing motifs (CpG DNA) to activate macrophages to produce nitric oxide (NO) and prostaglandin E(2) (PGE(2)) and to induce expression of NO synthase 2 (NOS2) and cyclooxygenase 2 (COX2). As little as 0.3 microg of CpG DNA/ml increased NO and PGE(2) production in a dose- and time-dependent fashion in cells of the mouse macrophage cell line J774. NO and PGE(2) production was noted by 4 to 8 h after initiation of cultures with the CpG DNA, with the kinetics of NO production induced by CpG DNA being comparable to that induced by a combination of lipopolysaccharide and gamma interferon. CpG DNA-treated J774 cells showed enhanced expression of NOS2 and COX2 proteins as determined by immunoblotting, with the relative potencies of the CpG DNAs generally corresponding to those noted for the induction of NO and PGE(2) production as well as to those noted for the induction of interleukin-6 (IL-6), IL-12, and tumor necrosis factor. Extracts from CpG DNA-treated cells converted L-arginine to L-citrulline, but the NOS inhibitor N(G)-monomethyl-L-arginine (NMMA) inhibited this reaction. The COX2-specific inhibitor NS398 inhibited CpG DNA-induced PGE(2) production and inhibited NO production to various degrees. The NOS inhibitors NMMA, 1400W, and N-iminoethyl-L-lysine effectively blocked NO production and increased the production of PGE(2) in a dose-dependent fashion. Thus, analogues of microbial DNA (i.e., CpG DNA) activate mouse macrophage lineage cells for the expression of NOS2 and COX2, with the production of NO and that of PGE(2) occurring in an interdependent manner.
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PMID:Host response to infection: the role of CpG DNA in induction of cyclooxygenase 2 and nitric oxide synthase 2 in murine macrophages. 1170 51

The ability of lung fibroblasts to modulate the immune response has been evaluated by analyzing the synthesis and release of interleukin (IL)-10 and IL-12 by lipopolysaccharide (LPS)-stimulated peripheral blood monocytes exposed to pulmonary fibroblast conditioned medium (FCM). IL-10 and IL-12 contents and gene expression were markedly modified by treatment with FCM as measured by ELISA (+97.5 +/- 12.8% and -68 +/- 7.3% for IL-10 and IL-12, respectively), immunocytochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR). These effects appeared to be mediated by prostaglandin E(2) (PGE(2)) as the modified release of both cytokines was reduced by treatment with indomethacin and mimicked by addition of exogenous PGE(2.) As a result of the enhanced production of IL-10, exposure of LPS/interferon (IFN)-gamma-activated monocytes to FCM was also able to reduce the expression of the class II major histocompatibility complex (MHC) molecule, human leukocyte-associated antigen-DR (HLA-DR) (-51.8 +/- 8.7%) and of the costimulatory molecule, CD40 (-53.9 +/- 11.7%). The expression of both molecules was completely restored when monocytes were pretreated with a neutralizing anti-IL-10 monoclonal antibody. The FCM obtained from fibrotic lung fibroblasts was instead less efficacious in potentiating LPS-stimulated IL-10 release and, consequently, in reducing HLA-DR and CD40 expression, suggesting that an impairment of the immune regulation operated by fibroblasts may be involved in the maintenance of chronic pulmonary inflammation.
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PMID:Normal human lung fibroblasts differently modulate interleukin-10 and interleukin-12 production by monocytes: implications for an altered immune response in pulmonary chronic inflammation. 1171 1

Macrophages play numerous roles in both physiologic and pathologic processes. Along with fibroblasts, they comprise the synovial tissue that forms the lining of musculoskeletal joint capsules and bursae, and they often envelop implants. During the process of phagocytosing prosthesis-related particles, macrophages in peri-implant tissue release inflammatory mediators. Little is known, however, about the response of these cells to mechanical perturbation, which often is a component of the physical environment of the cell. Mouse peritoneal macrophages were grown on a flexible membrane in vitro and a dynamic 1-Hz spatially uniform sinusoidal strain pattern imparted to the elastomeric substrate. The effect of mechanical strain on prostaglandin (PG) E(2) release was evaluated using cells that were activated by lipopolysaccharide (LPS) as well as by those that were not. The results are compared with the levels of PGE(2) stimulated by metallic particles. Strain magnitudes of 4 and 8% applied for 1 h resulted in almost a twofold increase in the release of PGE(2) from LPS-stimulated cells (p < 0.05) and nonstimulated macrophages (p < 0.07), compared with nonperturbated controls. No release was elicited by a challenge of metal particles. These findings demonstrate for the first time an effect of mechanical force on the release of an inflammatory mediator by macrophages. This response may help to explain the macrophage-mediated processes underlying the osteolysis associated with loose prostheses in bone and suggests a mechanism for the inflammation of synovial tissues by excessive mechanical strain.
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PMID:Effect of mechanical perturbation on the release of PGE(2) by macrophages in vitro. 1174 65

Advancement of cancer prevention and therapy requires clinical development of systemic biomarkers of pharmacological efficacy of the agent under scrutiny. Curcumin, a polyphenol derived from Curcuma spp., has shown wide-ranging chemopreventive activity in preclinical carcinogenic models, in which it inhibits cyclooxygenase (COX)-2 at the transcriptional level. COX-2 has been implicated in the development of many human cancers. To explore the inhibition of COX-2 activity as a systemic biomarker of drug efficacy, a biomarker of potential use in clinical trials of many chemopreventive drugs known to inhibit this enzyme, we measured COX-2 protein induction and prostaglandin E(2) (PGE(2)) production in human blood after incubation with lipopolysaccharide (LPS). When 1 microM curcumin was added in vitro to blood from healthy volunteers, LPS-induced COX-2 protein levels and concomitant PGE(2) production were reduced by 24% and 41%, respectively (P < 0.05 by ANOVA). To test whether effects on COX-2 activity could also be measured after oral dosing in humans, we conducted a dose-escalation pilot study of a standardized formulation of Curcuma extract in 15 patients with advanced colorectal cancer. Basal and LPS-mediated PGE(2) production was measured in blood, twice pretreatment and on days 1, 2, 8, and 29 of treatment. Analysis of basal and LPS-induced PGE(2) production during treatment demonstrated a trend toward dose-dependent inhibition (P < 0.005 by regression analysis), but there was no significant difference compared with values from pretreatment time points. Measurement of leukocyte COX-2 activity should be considered in clinical trials of other agents likely to inhibit this isozyme.
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PMID:Clinical development of leukocyte cyclooxygenase 2 activity as a systemic biomarker for cancer chemopreventive agents. 1175 48

We investigated the effects of FR122047 (1-[(4,5-bis(4-methoxyphenyl)-2-thiazoyl)carbonyl]-4-methylpiperazine hydrochloride), a selective cyclo-oxygenase (COX)-1 inhibitor, in rat type II collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). Using an ex vivo rat whole blood assay, FR122047 (0.032 - 3.2 mg kg(-1)) inhibited COX-1-derived thromboxane (TX) B(2) production with ED(50) value of 0.059 mg kg(-1), indicating that it was orally active, but did not inhibit lipopolysaccharide-induced prostaglandin (PG) E(2) production derived by COX-2. Oral administration of FR122047 showed a dose-dependent anti-inflammatory effect in rat CIA with ED(50) value of 0.56 mg kg(-1). This drug also dose dependently suppressed the levels of PGE(2) and TXB(2) in CIA rat paws with ED(50) values of 0.24 and 0.13 mg kg(-1), respectively. FR122047 had no effect in rat AIA model. In contrast, indomethacin, a non-selective COX inhibitor, was anti-inflammatory and reduced the formation of PGs in AIA rat paws. Unlike indomethacin, chronic treatment of FR122047 did not damage the stomach mucosa in CIA rats. These results demonstrate that COX-1 contributes to the oedema and the formation of PGE(2) and TXB(2) in rat CIA model, but not in rat AIA model. We conclude that FR122047 has an orally active and anti-inflammatory effect mediated by inhibition of PGE(2) and TXB(2) produced by COX-1 at a site of inflammation induced by type II collagen and it may be a useful tool for studying the involvement of COX-1 in various in vivo models of inflammation.
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PMID:Differential effect of FR122047, a selective cyclo-oxygenase-1 inhibitor, in rat chronic models of arthritis. 1183 26

The effects of an important new anti-inflammatory agent, the selective cyclooxygenase-2 inhibitor celecoxib, on bone resorption and osteoclastogenesis elicited by the inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), the endotoxin lipopolysaccharide (LPS), and the systemic hormones 1alpha,25-dihydroxyvitamin D(3) and parathyroid hormone were examined in vitro. Bone resorption was evaluated by measuring calcium released into the culture medium in a neonatal mouse calvarial bone organ culture. Osteoclastogenesis was evaluated by measuring tartrate-resistant acid phosphatase activity in the cells in cocultures of bone marrow cells and osteoblastic cells and in macrophage-colony-stimulating factor-dependent bone marrow cell cultures. Celecoxib (0.1 microM) completely inhibited the calcium release induced by IL-1beta, TNF-alpha, and LPS. The resorptive effect of 1alpha,25-dihydroxyvitamin D(3) was inhibited partially by celecoxib. In contrast, celecoxib did not inhibit the calcium release elicited by parathyroid hormone or prostaglandin E(2). Celecoxib (0.1 microM) also markedly inhibited osteoclastogenesis induced by these stimulators of bone resorption except for PGE(2) in the coculture system, whereas it failed to inhibit osteoclastogenesis in macrophage-colony-stimulating factor-dependent bone marrow cell cultures. These results indicate that, under certain conditions, cyclooxygenase-2-dependent prostaglandin synthesis is critical for the bone resorption induced by IL-1beta, TNF-alpha, and LPS, and for the osteoclastogenesis induced by these pro-inflammatory molecules and calciotropic hormones. The prevention of prostaglandin synthesis by inflammatory cytokines in bone cells could contribute to the efficacy of celecoxib in preventing bone loss in rheumatoid arthritis.
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PMID:Effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on bone resorption and osteoclastogenesis in vitro. 1185 3

The atrial natriuretic peptide (ANP) has been suggested to possess immunomodulatory potential because of its property to alter macrophage functions via its guanylate-cylcase- coupled A-receptor (NPR-A), such as inhibiting the expression of inducible nitric oxide synthase or TNF-alpha. The aim of this study was to investigate whether ANP influences COX-2. COX-2 expression in murine macrophages and in mice was induced by lipopolysaccharide. Release of PGE(2) and thromboxane B(2) was significantly reduced in the presence of ANP. C-type natriuretic peptide (CNP) also significantly reduced PGE(2)-accumulation in macrophages. Northern and Western blots showed that ANP attenuates COX-2 mRNA and protein. Reduction of neither COX-2 nor of PGE(2) production was significantly abrogated by an NPR-A antagonist, suggesting a pathway independent of cGMP. Furthermore, dibutyryl-cGMP did not affect PGE(2)-accumulation. cANF, the specific ligand for the natriuretic peptide (NP) clearance-receptor (NPR-C), significantly inhibited PGE(2)-production. Because some biological activities of ANP have been reported to be mediated via an NPR-C-mediated inhibition of adenylate-cyclase, we determined cAMP levels. ANP, CNP, and cANF significantly attenuated intracellular cAMP. In summary, ANP was shown to attenuate PGE(2)-production of lipopolysaccharide-activated macrophages predominantly via the NP clearance-receptor. ANP reduces COX-2-protein and -mRNA levels. The inhibition seems to be mediated via NPR-C and related to an attenuation of cAMP production.
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PMID:Inhibition of cyclooxygenase-2 by natriuretic peptides. 1186 6

Exposure to lead ions strongly enhances the susceptibility of rodents to endotoxin shock and parasitical infections. Macrophages play a key role during the immune response to lipopolysaccharide (LPS) and during the defense against parasites and might be a target of lead. In the present study, bone marrow-derived macrophages (BMMphi) pretreated with lead chloride prior to stimulation with LPS were analyzed for their release of immune mediators. Lead-pretreated cells released up to tenfold increased amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-12, and prostaglandin E(2) (PGE(2)) but less IL-10 compared with controls. These effects were paralleled by enhanced mRNA levels and were dependent on the duration of lead pretreatment. Inhibition of protein kinase C or of protein synthesis during the priming phase blocked the lead-induced increase of TNF-alpha and IL-6 release. In conclusion, lead ions prime BMMphi for enhanced proinflammatory cytokine secretion in response to LPS, likely by activation of protein kinase C and subsequent synthesis of an unidentified mediator.
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PMID:Enhanced proinflammatory response to endotoxin after priming of macrophages with lead ions. 1186 79

Secretory type IIA phospholipase A(2) (sPLA(2)-IIA) is a critical enzyme involved in inflammatory diseases. We have previously identified alveolar macrophages (AMs) as the major pulmonary source of lipopolysaccharide (LPS)-induced sPLA(2)-IIA expression in a guinea pig model of acute lung injury (ALI). Here, we examined the role of arachidonic acid (AA) in the regulation of basal and LPS-induced sPLA(2)-IIA expression in AMs. We showed that both AA and its nonmetabolizable analog, 5,8,11,14-eicosatetraynoic acid (ETYA), inhibited sPLA(2)-IIA synthesis in unstimulated AMs. However, only AA inhibited sPLA(2)-IIA expression in LPS-stimulated cells, suggesting that this effect requires metabolic conversion of AA. Indeed, cyclooxygenase inhibitors abolished this down-regulation. Prostaglandins PGE(2), PGA(2), and 15d-PGJ(2) also inhibited the LPS-induced sPLA(2)-IIA expression. Nuclear factor-kappaB (NF-kappaB) was found to regulate sPLA(2)-IIA expression in AMs. Both AA and ETYA inhibited basal activation of NF-kappaB but had no effect on LPS-induced NF-kappaB translocation, suggesting that suppression of sPLA(2)-IIA synthesis by AA in LPS-stimulated cells occurs via a NF-kappaB-independent pathway. 15-Deoxy-Delta(12,14)-PGJ(2) and ciglitazone, which are, respectively, natural and synthetic ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), inhibited LPS-induced sPLA(2)-IIA synthesis, whereas PPAR-alpha ligands were ineffective. Moreover, electrophoretic mobility shift assay showed PPAR activation by AA and PPAR-gamma ligands in LPS-stimulated AMs. Our results suggest that the down-regulation of basal sPLA(2)-IIA expression is unrelated to the metabolic conversion of AA but is dependent on the impairment of NF-kappaB activation. In contrast, the inhibition of LPS-stimulated sPLA(2)-IIA expression is mediated by cyclooxygenase-derived metabolites of AA and involves a PPAR-gamma-dependent pathway. These findings provide new insights for the treatment of ALI.
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PMID:Arachidonic acid differentially affects basal and lipopolysaccharide-induced sPLA(2)-IIA expression in alveolar macrophages through NF-kappaB and PPAR-gamma-dependent pathways. 1190 Dec 17

There is evidence of molecular cross talk between inflammatory mediators such as nitric oxide (NO) and prostaglandins (PG), which may regulate tissue homeostasis and contribute to pathophysiological processes. Here we examine the role of endogenous arachidonic acid (AA) and its AA metabolites in the regulation of NO release by lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7. Our results suggest that bromoenol lactone-sensitive phospholipase A(2) is involved in AA release and the subsequent PG and leukotriene (LT) production. The cyclooxygenase inhibitor, indomethacin, and lipoxygenase inhibitors such as baicalein and zileuton blocked the dose-dependent PGE(2) or LTB(4) and nitrite (NO(2)(-)) production induced by LPS. Furthermore, the effects of indomethacin were reverted by exogenous PGE(2) and forskolin, whereas AH23848B, an EP(4) PGE(2) subtype receptor antagonist, decreased NO(2)(-) release. On the other hand, the effect of baicalein on NO(-)(2) production was reverted by exogenous LTB(4) and the fibrate WY 14,643, a natural and a synthetic peroxisome proliferator-activated receptor alpha (PPAR alpha), respectively. Thus, PGE(2) via EP(4) receptor/cAMP and LTB(4) via PPAR alpha may be involved in the control of NO synthesis by LPS in macrophage RAW 264.7 cultures.
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PMID:Role of Ca(2+)-independent phospholipase A(2) and cyclooxygenase/lipoxygenase pathways in the nitric oxide production by murine macrophages stimulated by lipopolysaccharides. 1200 43


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