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)

Proteasomes, multisubunit complexes that consist of a 20S proteasome and a 19S regulatory complex, are essential for several cellular processes. Our interest in the proteasome complex stems from our observations that a novel photoactivable lipopolysaccharide (LPS) probe binds to specific proteasome subunits, and that LPS enhances the chymotrypsin-like activity of the proteasome to degrade synthetic peptides in vitro. Experiments with proteasome inhibitors have shown that expression of many LPS-inducible genes, including TLR2, is inhibited in macrophages. More important, proteasome inhibitors such as lactacystin can prevent LPS-induced shock in mice. This article focuses on the role of the proteasome in the development of inflammatory processes, which may result in septic shock, hemorrhagic shock, atherosclerosis, and neurodegenerative disorders. Taken collectively, the results suggest a potentially important role of the proteasome in inflammation and other macrophage functions.
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PMID:The proteasome: a central regulator of inflammation and macrophage function. 1588 15

Although vitamin B6 has been supposed to have anti-inflammatory effects, the molecular mechanism is not fully understood. To explore the mechanism of anti-inflammatory effects of vitamin B6, we have examined the effect of vitamin B6 on lipopolysaccharide (LPS)-stimulated inflammatory response in RAW 264.7 macrophages. This study demonstrated that vitamin B6 (pyridoxal) pretreatment of RAW cells inhibited LPS-induced expression of iNOS and COX-2 at the mRNA and protein levels. Vitamin B6 inhibited LPS-induced nuclear translocation of the NF-kappaB, the proinflammatory transcription factor, with reduction of the extent of LPS-induced IkappaBalpha degradation in RAW cells. Although vitamin B6 did not affect cellular proteasome activity, in vitro phosphorylation analysis with glutathione S-transferase-fused IkappaBalpha has shown that vitamin B6 suppressed LPS-induced IkappaB kinase activation. Furthermore, we demonstrated that elevating dietary vitamin B6 suppressed NO production in vivo in response to LPS administration. These observations suggest that the anti-inflammatory effect of vitamin B6 is mediated by suppression of NF-kappaB activation.
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PMID:Vitamin B6 suppresses NF-kappaB activation in LPS-stimulated mouse macrophages. 1627 88

Previously, we reported that expression of caveolin-1 in elicited peritoneal mouse macrophages was up-regulated by remarkably low (1.0-pg/ml) concentrations of Escherichia coli O111 lipopolysaccharide (LPS). Here we report that increases in caveolin-1 expression are manifested by different types of LPS, LPS-mimetic taxol, and heat-killed E. coli and to a much lesser extent by zymosan, polysaccharide-peptidoglycan, and heat-killed Staphylococcus aureus. Rhodobacter sphaeroides lipid A (RsDPLA) could not induce caveolin-1 expression in macrophages. Interestingly, polymyxin B (5 microg/ml) and RsDPLA show only a limited capacity to inhibit LPS-induced caveolin-1 expression. These findings suggest that expression of caveolin-1 in response to LPS may only partially be dependent upon lipid A. Recombinant tumor necrosis factor alpha marginally induces caveolin-1, suggesting that the ability of LPS to regulate caveolin-1 is not mediated primarily through an autocrine/paracrine mechanism involving this cytokine. Under conditions in which cellular levels of caveolin-1 are profoundly induced, no significant changes in TLR4 expression are observed. Of interest, caveolin-1 appears to localize to two cellular compartments, one associated with lipid rafts and a second associated with TLR4. Gamma interferon treatment inhibits the induction of caveolin-1 by LPS in macrophages. Inhibition of the p38 kinase-dependent pathway, but not the extracellular signal-regulated kinase pathway, effectively reduced the ability of LPS to mediate caveolin-1 up-regulation. Lactacystin, a potent inhibitor of the proteasome pathway, significantly modulates LPS-independent caveolin-1 expression, and lactacystin inhibits LPS-triggered caveolin-1 responses. These studies suggest that caveolin-1 up-regulation in response to LPS is likely to be proteasome dependent and triggered through the p38 kinase pathway.
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PMID:Regulation of cellular caveolin-1 protein expression in murine macrophages by microbial products. 1629 8

Evidence from the animal model suggests that proteasome inhibitors may have immunosuppressive properties; however, their effects on the human immune system remain poorly investigated. Here, we show that bortezomib, a proteasome inhibitor with anticancer activity, impairs several immune properties of human monocyte-derived dendritic cells (DCs). Namely, exposure of DCs to bortezomib reduces their phagocytic capacity, as shown by FITC-labeled dextran internalization and mannose-receptor CD206 down-regulation. DCs treated with bortezomib show skewed phenotypic maturation in response to stimuli of bacterial (lipopolysaccharide [LPS]) and endogenous sources (including TNF-alpha and CD40L), as well as reduced cytokine production and immunostimulatory capacity. LPS-induced CCL-2/MCP-1 and CCL5/RANTES secretions by DCs were prevented by DC treatment with bortezomib. Finally, CCR7 up-regulation in DCs exposed to LPS as well as migration toward CCL19/MIP-3beta were strongly impaired. As a suitable mechanism for these effects, bortezomib was found to down-regulate MyD88, an essential adaptor for TLR signaling, and to relieve LPS-induced activation of NF-kappaB, IRF-3, and IRF-8 and of the MAP kinase pathway. In summary, inhibition of DC function may represent a novel mechanism by which proteasome inhibitors exert immunomodulatory effects. These compounds could prove useful for tuning TLR signaling and for the treatment of inflammatory and immune-mediated disorders.
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PMID:Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. 1653 13

Bacterial infection elicits hypertriglyceridemia attributed to increased hepatic production of very low-density lipoprotein (VLDL) particles and decreased peripheral metabolism. The mechanisms underlying VLDL overproduction in sepsis are as yet unclear, but seem to be fed/fasted state-dependent. To learn more about this, we investigated hepatocytes isolated from fasted rats, made endotoxic by 1 mg/kg lipopolysaccharide (LPS) injection, for their ability to secrete the VLDL protein and lipid components. The results were then related to lipogenesis markers and expression of genes critical to VLDL biogenesis. Endotoxic rats showed increased levels of serum VLDL-apoB (10-fold), -triglyceride (2-fold), and -cholesterol (2-fold), whereby circulating VLDL were lipid-poor particles. Similarly, VLDL-apoB secretion by isolated endotoxic hepatocytes was approximately 85% above control, whereas marginal changes in the output of VLDL-lipid classes occurred. This was accompanied by a substantial rise in apoB and a moderate rise in MTP mRNA levels, but with basal de novo formation and efficiency of secretion of triglycerides, cholesterol and cholesteryl esters. These results indicate that during periods of food restriction, endotoxin does not enhance lipid provision to accomplish normal lipidation of overproduced apoB molecules, though this does occur to a sufficient extent to pass the proteasome checkpoint and secretion of lipid-poor, type 2 VLDL takes place.
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PMID:Impaired response of VLDL lipid and apoB secretion to endotoxin in the fasted rat liver. 1671 89

Our previous work demonstrated that the proteasome is central to most of genes induced by lipopolysaccharide. In this study, we evaluated the role of the proteasome in response to two other microbial stimuli, CpG DNA (bacterial DNA) and peptidoglycan (PG), by measuring the effect of proteasome inhibition on cytokine secretion, induction of inflammatory gene expression, and activation of mitogen-activated protein kinases (MAPK) in murine macrophages. Pretreatment of macrophage cultures with lactacystin, a well-established proteasome inhibitor, significantly repressed tumor necrosis factor alpha secretion and tumor necrosis factor alpha and interleukin 1 beta gene expression, blocked the degradation of IkappaB, and dysregulated phosphorylation of MAPK induced by CpG DNA or PG. With respect to MAPK, lactacystin blocked expression of PG- or CpG-induced phosphorylated ERK1 and ERK2 and increased expression of phosphorylated c-Jun amino-terminal kinase but had no significant effect on phosphorylated p38. Increased expression of phoshorylated c-Jun amino-terminal kinase did not lead to an increase in AP-1 binding activity. Collectively, these data strongly support the conclusion that the proteasome is a key regulator of the CpG DNA- and PG-induced signaling pathways.
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PMID:Proteasome-mediated regulation of CpG DNA- and peptidoglycan-induced cytokines, inflammatory genes, and mitogen-activated protein kinase activation. 1672 Dec 67

Indoleamine 2,3-dioxygenase (IDO) is a heme-containing enzyme, which catalyzes the initial and rate-determining step of L-tryptophan (L-Trp) metabolism via the kynurenine pathway in nonhepatic tissues. Similar to inducible nitric oxide synthase (iNOS), IDO is induced by interferon-gamma and lipopolysaccharide in the inflammatory response. In vivo studies indicate that the nitric oxide (NO) produced by iNOS inhibits IDO activity by directly interacting with it and by promoting its degradation through the proteasome pathway. In this work, the molecular mechanisms underlying the interactions between NO and human recombinant IDO (hIDO) were systematically studied with optical absorption and resonance Raman spectroscopies. Resonance Raman data show that the heme prosthetic group in the NO-bound hIDO is situated in a unique protein environment and adopts an out-of-plane deformed geometry that is sensitive to L-Trp binding. Under mildly acidic conditions, the proximal heme iron-His bond is prone to rupture, resulting in a five-coordinate (5C) NO-bound species. The bond breakage reaction induces significant conformational changes in the protein matrix, which may account for the NO-induced inactivation of hIDO and its enhanced proteasome-linked degradation in vivo. Moreover, it was found that the NO-induced bond breakage reaction occurs more rapidly in the ferrous protein than in the ferric protein and is fully inhibited by L-Trp binding. The spectroscopic data presented here not only provide the first glimpse of the possible regulatory mechanism of hIDO by NO in the cell at the molecular level, but they also suggest that the NO-dependent regulation can be modulated by cellular factors, such as the NO abundance, pH, redox environment, and L-Trp availability.
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PMID:Interactions between nitric oxide and indoleamine 2,3-dioxygenase. 1683 26

Misfolded proteins can be directed into cytoplasmic aggregates such as aggresomes and dendritic cell aggresome-like induced structures (DALIS). DALIS were originally identified in lipopolysaccharide-stimulated dendritic cells and act as storage compartments for polyubiquitinated Defective Ribosomal Products (DRiPs) prior to their clearance by the proteasome. Here we demonstrate that ubiquitinated protein aggregates that are similar to DALIS, and not related to aggresomes, can be observed in several cell types in response to stress, including oxidative stress, transfection, and starvation. Significantly, both immune and nonimmune cells could form these aggresome-like induced structures (ALIS). Protein synthesis was essential for ALIS formation in response to oxidative stress, indicating that DRiP formation was required. Furthermore, puromycin, which increases DRiP formation, was sufficient to induce ALIS formation. Inhibition of either proteasomes or of autophagy interfered with ALIS clearance in puromycin treated cells. Autophagy inhibition enhanced ALIS formation under a variety of stress conditions. During starvation, ALIS formation in autophagy-deficient cells was only partially inhibited by protein synthesis inhibitors, indicating that both long-lived proteins and DRiPs can be targeted to ALIS. Together, these findings demonstrate that ALIS act as generalized stress-induced protein storage compartments for substrates of the proteasome and autophagy.
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PMID:ALIS are stress-induced protein storage compartments for substrates of the proteasome and autophagy. 1687 9

The serine anti-protease elafin is expressed by monocytes, alveolar macrophages, neutrophils, and at mucosal surfaces and possesses antimicrobial activity. It is also known to reduce lipopolysaccharide-induced neutrophil influx into murine alveoli as well as to abrogate lipopolysaccharide-induced production of matrix metalloprotease 9, macrophage inhibitory protein 2, and tumor necrosis factor-alpha by as-yet unidentified mechanisms. In this report we have shown that elafin inhibits the lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in monocytes by inhibiting AP-1 and NF-kappaB activation. Elafin prevented lipopolysaccharide-induced phosphorylation of AP-1, c-Jun, and JNK but had no effect on phosphorylation of p38. The lipopolysaccharide-induced degradation of IL-1R-associated kinase 1, IkappaBalpha, and IkappaBbeta was inhibited by elafin but phosphorylation of IkappaBalpha was unaffected. Polyubiquitinated protein including polyubiquitinated IkappaBalpha was shown to accumulate in the presence of elafin. These results suggest that inhibition by elafin of lipopolysaccharide-induced AP-1 and NF-kappaB activation occurs via an effect on the ubiquitin-proteasome pathway.
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PMID:Elafin prevents lipopolysaccharide-induced AP-1 and NF-kappaB activation via an effect on the ubiquitin-proteasome pathway. 1698 Mar 10

We have previously demonstrated that challenge of rat or mice with lipopolysaccharide (LPS) in vivo promotes Sp1 protein degradation. The protease responsible for the LPS-induced Sp1 degradation has not been identified. In this study, we have identified, characterized and partially purified an LPS-inducible Sp1-degrading enzyme (LISPDE) activity from rat lungs. LISPDE activity selectively degraded Sp1, but not nuclear protein, C-fos, p65, I-kappaBalpha and protein actin. Nuclear extract contains approximately 14-fold of the LISPDE activity as that detected in cytoplasmic extract, suggesting that LISPDE is predominantly a nuclear protease. Using biochemical reagents, protease inhibitors and peptide substrates, we have characterized the LISPDE activity. Based on biochemical characteristics, inhibitor profile, and substrate specificity, we have shown that LISPDE activity is not 26S proteasome, caspase or cathepsin-like activity, but is a trypsin-like serine protease activity. Using soybean trypsin inhibitor (SBTI)-sepharose affinity column, we have partially purified the LISPDE protein, which has an estimated molecular mass of 33 kDa and selectively degrades native Sp1 protein. We mapped the initial site for proteolytic cleavage of Sp1 by LISPDE to be located within the region between amino acids 181-328. We conclude that LPS causes Sp1 degradation by inducing a unique trypsin-like serine protease, LISPDE.
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PMID:Lipopolysaccharide causes Sp1 protein degradation by inducing a unique trypsin-like serine protease in rat lungs. 1709 79


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