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)

We investigated the inhibition of IkappaB kinase (IKK) activity in lipopolysaccharide (LPS)-activated murine macrophages (RAW 264.7 cell line) by various polyphenols including (-)-epigallocatechin-3-gallate, theaflavin, a mixture of theaflavin-3 gallate and theaflavin-3'-gallate, theaflavin-3,3'-digallate (TF-3), pyrocyanidin B-3, casuarinin, geraniin, and penta-O-galloyl-beta-D-glucose (5GG). TF-3 inhibited IKK activity in activated macrophages more strongly than did the other polyphenols. TF-3 strongly inhibited both IKK1 and IKK2 activity and prevented the degradation of IkappaBalpha and IkappaBbeta in activated macrophage cells. The results suggested that the inhibition of IKK activity by TF-3 could occur by a direct effect on IKKs or on upstream events in the signal transduction pathway. Furthermore, geraniin, 5GG, and TF-3 all blocked phosphorylation of IKB from the cytosolic fraction, inhibited nuclear factor-kappaB (NFkappaB) activity, and inhibited increases in inducible nitric oxide synthase levels in activated macrophages. These results suggest that TF-3 may exert its anti-inflammatory and cancer chemopreventive actions by suppressing the activation of NFkappaB through inhibition of IKK activity.
 ...
PMID:Suppression of lipopolysaccharide-induced nuclear factor-kappaB activity by theaflavin-3,3'-digallate from black tea and other polyphenols through down-regulation of IkappaB kinase activity in macrophages. 1064 43

Activation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) and gamma interferon (IFN-gamma) induces the expression of gene products involved in host defense, among them type 2 nitric oxide synthase. Treatment of cells with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) inhibited the LPS- and IFN-gamma-dependent synthesis of NO, a process that was not antagonized by similar concentrations of prostaglandin J(2), prostaglandin E(2), or rosiglitazone, a peroxisomal proliferator-activated receptor gamma ligand. Incubation of activated macrophages with 15dPGJ(2) inhibited the degradation of IkappaBalpha and IkappaBbeta and increased their levels in the nuclei. NF-kappaB activity, as well as the transcription of NF-kappaB-dependent genes, such as those encoding type 2 nitric oxide synthase and cyclooxygenase 2, was impaired under these conditions. Analysis of the steps leading to IkappaB phosphorylation showed an inhibition of IkappaB kinase by 15dPGJ(2) in cells treated with LPS and IFN-gamma, resulting in an impaired phosphorylation of IkappaBalpha, at least in the serine 32 residue required for targeting and degradation of this protein. Incubation of partially purified activated IkappaB kinase with 2 microM 15dPGJ(2) reduced by 83% the phosphorylation in serine 32 of IkappaBalpha, suggesting that this prostaglandin exerts direct inhibitory effects on the activity of the IkappaB kinase complex. These results show rapid actions of 15dPGJ(2), independent of peroxisomal proliferator receptor gamma activation, in macrophages challenged with low doses of LPS and IFN-gamma.
 ...
PMID:Inhibition of IkappaB kinase and IkappaB phosphorylation by 15-deoxy-Delta(12,14)-prostaglandin J(2) in activated murine macrophages. 1066 46

Sodium valproate (VPA) is frequently used to treat epilepsy and convulsive disorders. Several reports have indicated that anti-epileptic drugs (AED) affect the immune system, but the mechanism has not been clear. We examined whether the commonly used AEDs, diazepam (DZP), carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and VPA, can inhibit activation of the nuclear transcription factor kappa B (NF-kappaB), in human monocytic leukemia cells (THP-1) and in human glioma cells (A-172). NF-kappaB is essential to the expression of the kappa light chain of immunoglobulin and proinflammatory cytokines. Electrophoretic mobility shift assays (EMSA) of nuclear extracts demonstrated that VPA inhibits NF-kappaB activation induced by lipopolysaccharide (LPS), but the other AEDs do not. Western blot analysis revealed that this inhibition is not linked to preservation of expression of IkappaBalpha protein. Chloramphenicol acetyltransferase (CAT) assay indicated that NF-kappaB-dependent reporter gene expression is suppressed in glioma cells pretreated with VPA. VPA significantly inhibited LPS-induced production of TNF-alpha and IL-6 by THP-1 cells, whereas other AEDs did not. The findings are consistent with the idea that VPA suppresses TNF-alpha and IL-6 production via inhibition of NF-kappaB activation. Our results suggest that VPA can modulate immune responses in vitro. These findings raise the possibility that such modulation might occur with clinical use of VPA.
 ...
PMID:Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. 1070 May 73

Fractalkine is an endothelial cell-derived CX3C chemokine that is chemotactic mainly to mononuclear cells. Fractalkine was induced in rat aortic endothelial cells (RAEC) by interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and lipopolysaccharide (LPS) transcriptionally and translationally. This induction correlated with increased NF-kappaB DNA binding activity as determined by gel mobility shift assay. Supershift assays revealed that the NF-kappaB subunits p50 and p65 were responsible for kappaB binding. Accordingly, we examined the role of NF-kappaB in fractalkine induction in RAEC through the use of an adenovirus-mediated mutant IkappaB as a specific inhibitor. Delivery of a dominant-negative form of IkappaBalpha in RAEC dramatically reduced the induction of fractalkine by these stimuli, suggesting a role for NF-kappaB activation in fractalkine induction. The inhibition of fractalkine expression by two potent NF-kappaB inhibitors, sulfasalazine and sanguinarine, further supported the central role of NF-kappaB in fractalkine transcription regulation and suggested a novel therapeutic target aimed at modulating leukocyte endothelial cell interaction.
 ...
PMID:NF-kappaB-dependent fractalkine induction in rat aortic endothelial cells stimulated by IL-1beta, TNF-alpha, and LPS. 1077 Feb 92

Systemic injection of the endotoxin lipopolysaccharide (LPS) upregulates the gene encoding CD14 early in the circumventricular organs (CVOs) and later in the brain parenchyma. The present study tested the hypothesis that the parenchymal production of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) by microglial cells is responsible for triggering CD14 transcription in an autocrine/paracrine loop-like manner. In a first set of experiments, Sprague Dawley rats were killed 1, 3, 6, and 12 hr after an intracerebroventricular administration of recombinant rat TNF-alpha or vehicle solution. Second, anti-rat TNF-alpha-neutralizing antibody or vehicle solution was administrated into the lateral ventricle 10 hr before an intraperitoneal injection of LPS. Central administration of the cytokine caused a strong induction of IkappaBalpha, TNF-alpha, and CD14 mRNA in parenchymal microglial cells. The hybridization signal for these transcripts was localized to the edge of the ventricles and the site of infusion. The time-related expression of each mRNA suggested that TNF-alpha has the ability to trigger its own production followed by the transcription of the LPS receptor; the signal for IkappaBalpha, TNF-alpha, and CD14 peaked at 1, 3, and 6 hr, respectively. The genes encoding TNF-alpha and mCD14 were also induced in the CVOs and within microglial cells across the brain parenchyma in response to intraperitoneal LPS administration. This induction in parenchymal cells of the brain was prevented in animals that received the anti-TNF-antisera intracerebroventricularly 10 hr before the systemic treatment with the endotoxin. The present data provide the evidence that microglial-derived TNF-alpha is responsible for the production of the LPS receptor CD14 during endotoxemia. This autocrine/paracrine stimulatory loop may be of great importance in controlling the inflammatory events that take place in the CNS during innate immune response as well as under pathological conditions.
 ...
PMID:Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor kappa B activity in the brain during endotoxemia. 1077 9

Ceramide has been implicated as an intermediate in the signal transduction of several cytokines including tumor necrosis factor (TNF). Both ceramide and TNF activate a wide variety of cellular responses, including NF-kappaB, AP-1, JNK, and apoptosis. Whether ceramide transduces these signals through the same mechanism as TNF is not known. In the present study we investigated the role of the T cell-specific tyrosine kinase p56(lck) in ceramide- and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, isogeneic Lck-deficient T cells. Treatment with ceramide activated NF-kappaB, degraded IkappaBalpha, and induced NF-kappaB-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56(lck) kinase. These effects were specific to ceramide, as activation of NF-kappaB by phorbol 12-myristate 13-acetate, lipopolysaccharide, H(2)O(2), and TNF was minimally affected. p56(lck) was also found to be required for ceramide-induced but not TNF-induced AP-1 activation. Similarly, ceramide activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. Ceramide also induced cytotoxicity and activated caspases and reactive oxygen intermediates in Jurkat cells but not in JCaM1 cells. Ceramide activated p56(lck) activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56(lck) tyrosine kinase reversed the ceramide-induced NF-kappaB activation and cytotoxicity. Overall our results demonstrate that p56(lck) plays a critical role in the activation of NF-kappaB, AP-1, JNK, and apoptosis by ceramide but has minimal or no role in activation of these responses by TNF.
 ...
PMID:Protein tyrosine kinase p56lck is required for ceramide-induced but not tumor necrosis factor-induced activation of NF-kappa B, AP-1, JNK, and apoptosis. 1078 36

Whether all inflammatory agents activate nuclear transcription factors NF-kappaB and activated protein-1 (AP-1) through the same mechanism is not known. We examined the effect of the phosphatidylinositol-3-kinase (PI-3K) inhibitor wortmannin on the activation of NF-kappaB and AP-1 by different inflammatory agents. Wortmannin blocked NF-kappaB and AP-1 activation by lipopolysaccharide and phorbol ester but had minimal effect on activation by hydrogen peroxide, ceramide, okadaic acid and tumor necrosis factor. Inhibition of NF-kappaB correlated with abrogation of the degradation of IkappaBalpha and of NF-kappaB-dependent reporter gene transcription. Thus, the mechanism of NF-kappaB and AP-1 activation by lipopolysaccharide and phorbol ester involves PI-3K.
 ...
PMID:Wortmannin inhibits activation of nuclear transcription factors NF-kappaB and activated protein-1 induced by lipopolysaccharide and phorbol ester. 1080 70

Humic acid (HA), a potential toxin when penetrating the drinking well water of blackfoot disease-endemic areas in Taiwan, has been implicated as one of the etiological factors of this disease. In this study, we investigated the effects of HA on the expression of human vascular endothelial-leukocyte adhesion molecules and the activation of nuclear factor kappa B (NF-kappaB) in cultured human umbilical vein endothelial cells (HUVECs). The expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin was monitored by flow cytometry. Pretreatment of HUVECs with HA inhibited the lipopolysaccharide (LPS)-induced expression of these three adhesion molecules in a dose- and time-dependent manner. Since NF-kappaB can regulate the expression of these adhesion molecules, NF-kappaB activation was assessed by electrophoretic mobility shift assay (EMSA). Our results reveal that the activation of NF-kappaB by LPS is suppressed by HA in a dose- and time-dependent manner. Furthermore, HA reduces NF-kappaB binding to DNA slightly, but completely inhibits the degradation of IkappaBalpha at a concentration of 100 microg/ml. Thus, all our data demonstrate that HA can inhibit the LPS-induced expression of adhesion molecules through the inhibition of NF-kappaB activation. HA may also suppress the immune or inflammatory reaction of HUVECs responsible for endotoxin, which could be one possible explanation for the causes of the infection and inflammation observed for patients with blackfoot disease. Our results also suggest that immune or inflammatory disturbance occurs for patients with blackfoot disease and that NF-kappaB may be a critical molecule in the pathogenesis of this disease.
 ...
PMID:Humic acid suppresses the LPS-induced expression of cell-surface adhesion proteins through the inhibition of NF-kappaB activation. 1087 19

The antiatherogenic effect of estrogen is mediated, in part, by inhibitory effects on endothelial vascular cell adhesion molecule-1 (VCAM-1) expression. To determine the mechanism by which estrogen regulates VCAM-1 expression, we compared the effect of 17beta-estradiol (E(2)) and of the glucocorticoid dexamethasone (Dex) on lipopolysaccharide (LPS)-induced VCAM-1 expression in human endothelial cells. E(2) decreased LPS-induced VCAM-1 mRNA and protein expression to a greater extent than Dex. Dex, but not E(2), stabilized VCAM-1 mRNA. This correlated with inhibition of monocytoid U937 cell adhesion to endothelial cells. Transfection of endothelial cells with a functional VCAM-1 promoter construct showed that E(2) inhibited LPS-induced VCAM-1 gene transcription more potently than did Dex. However, using a truncated construct containing only the nuclear factor-kappaB (NF-kappaB)-responsive elements but lacking the consensus sequences for activator protein-1 (AP-1) and GATA, E(2) and Dex had similar inhibitory effects. Consistently, gel-shift assays showed that E(2) and Dex comparably inhibit LPS-induced activation of NF-kappaB, whereas E(2) inhibited LPS-induced activation of AP-1 and GATA to a greater extent than Dex. E(2) inhibition of NF-kappaB after LPS treatment was associated with decreased inhibitor kappaB (IkappaB) kinase activity and with a stabilization of the NF-kappaB inhibitor IkappaBalpha. These results indicate that E(2) decreases VCAM-1 gene expression through the inhibition of NF-kappaB, AP-1, and GATA and suggest novel mechanisms for the antiatherogenic effect of estrogen on the vascular wall.
 ...
PMID:Estrogens and glucocorticoids inhibit endothelial vascular cell adhesion molecule-1 expression by different transcriptional mechanisms. 1088 67

Chlorophyllin (CHL), a water-soluble derivative of chlorophyll, functions as an anticarcinogen and antioxidant. In the present study, we investigated the effect of CHL on nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Treatment with CHL inhibited nitric oxide production in the LPS-stimulated RAW 264. 7 cells in a dose-related manner. Competitive RT-PCR analysis, using a DNA competitor as an internal standard, demonstrated that the treatment with 1, 10, and 50 microM CHL decreased LPS-induced iNOS mRNA expression in a concentration-dependent manner. Since the expression of the iNOS gene is mainly regulated by NF-kappaB, we then examined the effects of CHL on the NF-kappaB DNA binding activity, using an electrophoretic mobility shift assay. CHL down-regulated the NF-kappaB DNA binding on its cognate recognition site at the concentrations just noted. Employing a transfection and reporter gene expression system with p(NF-kappaB)(3)-chloramphenicol acetyl transferase (CAT), the treatment of CHL produced a dose-dependent inhibition of CAT activity in RAW 264.7 cells. Furthermore, CHL partially restored LPS-decreased IkappaBalpha, an inhibitory protein against NF-kappaB activation, in the cytosolic extract from the LPS-treated cells determined by immunoblot analysis. CHL also protected the hydroxyl radical-induced cytotoxicity in RAW 264.7 cells, indicating its antioxidant effect. These results suggest that CHL suppresses the nitric oxide production and iNOS mRNA expression mediated by the inhibition of NF-kappaB activation, and its action mechanism may be based on its antioxidant effect.
 ...
PMID:Chlorophyllin suppression of lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells. 1089 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>