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)

Systems for protein degradation are essential for tight control of the inflammatory immune response. Autophagy, a bulk degradation system that delivers cytoplasmic constituents into autolysosomes, controls degradation of long-lived proteins, insoluble protein aggregates and invading microbes, and is suggested to be involved in the regulation of inflammation. However, the mechanism underlying the regulation of inflammatory response by autophagy is poorly understood. Here we show that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice. Atg16L1-deficiency disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane, resulting in a loss of microtubule-associated protein 1 light chain 3 (LC3) conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins are severely impaired in Atg16L1-deficient cells. Following stimulation with lipopolysaccharide, a ligand for Toll-like receptor 4 (refs 8, 9), Atg16L1-deficient macrophages produce high amounts of the inflammatory cytokines IL-1beta and IL-18. In lipopolysaccharide-stimulated macrophages, Atg16L1-deficiency causes Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent activation of caspase-1, leading to increased production of IL-1beta. Mice lacking Atg16L1 in haematopoietic cells are highly susceptible to dextran sulphate sodium-induced acute colitis, which is alleviated by injection of anti-IL-1beta and IL-18 antibodies, indicating the importance of Atg16L1 in the suppression of intestinal inflammation. These results demonstrate that Atg16L1 is an essential component of the autophagic machinery responsible for control of the endotoxin-induced inflammatory immune response.
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PMID:Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. 1884 65

The transcription and protein expression of many cytochrome P450 (P450) genes are down-regulated in animal models of inflammation and infection. We determined previously that hepatic P450 mRNAs are selectively regulated in a mouse model of enteropathogenic bacterial infection, and that this regulation was not dependent on the lipopolysaccharide (LPS) receptor protein toll-like receptor 4 (TLR4). In the dextran sulfate sodium (DSS) model of chemically induced inflammatory bowel disease (IBD), the reduction in activities of several hepatic P450 enzymes were concluded to be partially dependent on LPS from commensal bacteria [Masubuchi Y, Horie T. Endotoxin-mediated disturbance of hepatic cytochrome P450 function and development of endotoxin tolerance in the rat model of dextran sulfate sodium-induced experimental colitis. Drug Metab Dispos 2004;32:437-441]. In the present study, we sought to determine whether colitis induced by LPS regulates hepatic P450 mRNA and protein expression similarly to infectious colitis, and to determine the role of TLR4 in the response to DSS colitis. The role of LPS in the response to DSS was further examined by comparison with the effects of injected LPS. We demonstrate that administration of DSS results in the down-regulation of multiple P450 enzymes in mouse liver. However, there are discernable differences in the pattern of P450 expression in the two models. Some effects of DSS-induced colitis are TLR4-dependent, and others are not. In contrast, the effects of injected LPS on hepatic P450 mRNA expression are entirely TLR4-dependent. Thus, our results indicate that the pattern of hepatic P450 expression, and the mechanism of regulation, during inflammation of the bowel depend on the etiology of the disease.
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PMID:TLR4-dependent and -independent regulation of hepatic cytochrome P450 in mice with chemically induced inflammatory bowel disease. 1902 21

Cow milk contains a large amount of an immunoregulatory cytokine, transforming growth factor-beta (TGFbeta). The present study investigated whether commercially available pasteurized cow milk retains TGFbeta activity both in vitro and in vivo. Some commercial cow milk increased TGFbeta/Smad-responsive reporter activity and induced Smad2 phosphorylation and the transcription of the TGFbeta/Smad target genes TGFbeta itself and Smad7 in vitro. Mice treated orally with 500 microL of cow milk containing TGFbeta (3 microg/L) daily for 2 wk had increased phosphorylation of Smad2 and TGFbeta and Smad7 mRNA expression in the intestine. These mice also had significantly greater serum TGFbeta concentrations than the mice treated orally with PBS. Furthermore, oral administration of 500 microL of cow milk containing TGFbeta (3 microg/L) daily for 2 wk before the induction of dextran sodium sulfate colitis and lipopolysaccharide-induced endotoxemia ameliorated tissue damage and mortality, respectively, in mice. These in vivo effects of cow milk were abrogated by the simultaneous administration of TGFbeta type I receptor kinase inhibitor with the cow milk, and they were not observed after the oral administration of cow's milk containing little TGFbeta. In humans, 1 oral challenge of 10 mL/kg cow milk containing TGFbeta (3 microg/L) increased the plasma TGFbeta concentrations at 4 h after the challenge. Thus, some commercially available pasteurized cow milk retains TGFbeta activity, which may be able to provide protection against experimental colitis and endotoxemia associated with increased intestinal and circulating TGFbeta levels.
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PMID:Transforming growth factor-beta activity in commercially available pasteurized cow milk provides protection against inflammation in mice. 1905 55

The objective of the study was to investigate the regulation of hepatic flavin-containing monooxygenases (Fmo) Fmo1, Fmo3, Fmo4, and Fmo5 in three different mouse models of inflammation, including treatment with Citrobacter rodentium, lipopolysaccharide (LPS), and dextran sulfate sodium (DSS). Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate the steady-state mRNA levels for the various Fmo isoforms in these mouse models of inflammation during different treatment time courses. Fmo3 mRNA was most significantly down-regulated in C. rodentium-treated female mice. Fmo1, Fmo3, and Fmo5 mRNAs were also found to be down-regulated in LPS models of inflammation. The significant down-regulation of hepatic FMO3 protein during C. rodentium treatment was confirmed with Western blot analysis of liver microsomes from treated animals. Toll-like receptor (TLR) 4 is known to be responsible for LPS signaling in association with several proteins. To investigate whether TLR4 was responsible for regulation of Fmo genes in both LPS and C. rodentium animal models, Fmo mRNA levels in female wild-type (C3H/HeOuJ) and TLR4 mutant (C3H/HeJ) mice were compared in both inflammatory models by real-time RT-PCR. The results showed that Fmo3 down-regulation during C. rodentium infection is independent of TLR4. Whereas TLR4 is likely to play only a partial role in Fmo1 gene regulation in LPS-treated animals, our results show that the down-regulation of Fmo3 and Fmo5 in this model is TLR4-dependent. Unlike cytochrome P450 regulation measured in the same mouse strains, Fmo3 expression was largely refractory to down-regulation in the DSS model of inflammatory colitis.
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PMID:Hepatic flavin-containing monooxygenase gene regulation in different mouse inflammation models. 1908 65

NHE8 transporter is a member of the sodium/hydrogen exchanger (NHE) family. This transporter protein is expressed at the apical membrane of epithelial cells of kidney and intestine and contributes to vectorial Na(+) transport in both tissues. Although NaCl absorption has been shown to be reduced in diarrhea associated with colitis and enteritis, little is known about the role of Na(+)/H(+) exchange and the involvement of NHE isoforms in the pathogenesis of inflammatory disorders and the mechanism of inflammation-associated diarrhea. This study investigated the role of NHE8 in the setting of inflammatory states. Jejunal mucosa was harvested from trinitrobenzene sulfonic acid (TNBS) colitis rats or lipopolysaccharide (LPS) rats for RNA extraction and brush-border membrane protein purification. The human NHE8 gene promoter was cloned from human genomic DNA and characterized in Caco-2 cells. The promoter was further used to study the mechanisms of TNF-alpha-mediated NHE8 expression downregulation in Caco-2 cells. Results from Western blot and real-time PCR indicated that NHE8 protein and mRNA were significantly reduced in TNBS rats and LPS rats. In Caco-2 cells, TNF-alpha produces similar reduction levels in the endogenous NHE8 mRNA expression observed in our in vivo studies. The downregulation of NHE8 expression mediated by TNF-alpha could be blocked by transcription inhibitor actinomycin D, suggesting the involvement of transcriptional regulation. Further studies indicated that the human NHE8 gene transcription could be activated by Sp3 transcriptional factor, and TNF-alpha inhibits human NHE8 expression by reducing Sp3 interaction at the minimal promoter region of the human NHE8 gene. In conclusion, our studies suggest that TNF-alpha decreases NHE8 expression in inflammation induced by TNBS and LPS, which may contribute to the diarrhea associated with inflammation.
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PMID:Tumor necrosis factor-{alpha} downregulates intestinal NHE8 expression by reducing basal promoter activity. 1910 23

Bacterial DNA motifs (such as CpG-oligodeoxynucleotides: CpG-ODN) induce innate immune responses via binding to Toll-like-receptor-9 (TLR-9). In murine intestinal mucosa treatment with CpG-ODN worsens chronic intestinal inflammation, whereas it prevents or ameliorates colitis when given in a prophylactic setting. In tonsils B cells have been reported to express TLR-9, especially after activation. Whether B cells in the human intestinal mucosa also express TLR-9 and whether their function can be influenced by CpG-ODN is, so far, unknown. Mucosal B cells were isolated according to a new protocol from surgical specimens of patients with inflammatory bowel disease and from controls by collagenase digestion followed by magnetic cell sorting using anti-CD19 antibody armed magnetic beads. TLR-9 mRNA and protein expression were quantified by real-time polymerase chain reaction (PCR) and Western blot, respectively. Immunoglobulin A (IgA) secretion was measured by enzyme-linked immunosorbent assay after stimulation of isolated B cells with CpG-ODN, control GpC-ODN or lipopolysaccharide (LPS). Flow cytometric analysis of the isolated lamina propria mononuclear cells showed a purification of 73% (+/-22%) CD19(+) cells. By quantitative reverse transcription-PCR and by Western blot TLR-9 expression in this cell population was evident. IgA secretion was increased significantly by CpG-ODN incubation compared with GpC-ODN and LPS. Compared with unstimulated controls, CpG-ODN up-regulated IgA secretion to 139% (+/-21%). These data demonstrate that CD19(+) mucosal B cells express TLR-9 and secrete increased levels of IgA upon stimulation with CpG-ODN, indicating an additional link between adaptive and innate intestinal immune responses.
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PMID:CpG-oligodeoxynucleotides stimulate immunoglobulin A secretion in intestinal mucosal B cells. 1922 Aug 39

Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine; ET-18-OCH(3)) is an antitumor alkyl-lysophospholipid analog that binds lipid rafts, altering their protein composition (J Exp Med 200:353-365). Because L-selectin locates in lipid rafts and plays a crucial role in the recruitment of leukocytes into inflamed tissues, we hypothesized that edelfosine might affect inflammation by modulating L-selectin and inflammatory cell migration. Here, we have found that edelfosine inhibited neutrophil-endothelium interaction through L-selectin shedding. Oral treatment of edelfosine diminished inflammation in two murine animal models. Edelfosine showed a higher antiinflammatory effect than the nonsteroidal anti-inflammatory drug (NSAID) indomethacin in the bentonite mouse-paw edema model. Using a rat model of experimental colitis, edelfosine oral administration ameliorated the clinical and histopathologic severity of the inflammatory colitis with a dramatic decrease in mucosal damage and neutrophil infiltration. Colon sections from edelfosine-treated rats showed a remarkable reduction in ulcer formation, edema, and inflammatory cell infiltration. Edelfosine enhanced lipopolysaccharide-induced expression of anti-inflammatory interleukin-10 in mouse macrophages. Edelfosine oral treatment in rats, at doses 8-fold higher than those displaying anti-inflammatory action, lacked toxicity. Edelfosine treatment showed no any significant cardiotoxicity, hepatotoxicity or renal toxicity. Unlike NSAIDs, edelfosine did not inhibit prostaglandin E(2) synthesis in gastrointestinal mucosal biopsies, and no histologic alteration in gastrointestinal tract was detected after drug treatment. Thus, edelfosine shows a potent in vitro and in vivo anti-inflammatory activity while sparing gastric mucosa. Our data identify edelfosine as a novel anti-inflammatory drug by abating neutrophil infiltration through L-selectin shedding and may provide a new therapeutic approach for inflammatory bowel disease free from toxicity.
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PMID:Novel anti-inflammatory action of edelfosine lacking toxicity with protective effect in experimental colitis. 1924 50

Inflammatory bowel disease (IBD) is characterized by heavy production of proinflammatory cytokines such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Interactions of the autonomic nervous system with local immune cells play an important role in the development of IBD, and the balance of autonomic nerve function is broken in IBD patients with sympathetic overactivity. However, the function of catecholamines in the progress of colitis is unclear. In this study, we examined the role of catecholamines via alpha2-adrenoreceptor in acute murine colitis. The expression of tyrosine hydroxylase (TH) and dopamine b-hydroxylase (DBH), two rate-limiting enzymes in catecholamine synthesis, was detected by immunohistochemistry in murine colitis. Murine colitis was induced by dextran sodium sulphate or trinitrobenzene sulphonic acid (TNBS), and the mice were administered RX821002 or UK14304, alpha2-adrenoceptor antagonists or agonists. Colitis was evaluated by clinical symptoms, myeloperoxidase assay, TNF-alpha and IL-1beta production and histology. Lamina propria mononuclear cells (LPMCs) from mice with TNBS colitis were cultured in the absence or presence of RX821002 or UK14304, and stimulated further by lipopolysaccharide. TH and DBH are induced in LPMCs of inflamed colon, the evidence of catecholamine synthesis during the process of colitis. RX821002 down-regulates the production of proinflammatory cytokines from LPMCs, while UK14304 leads to exacerbation of colitis. Together, our data show a critical role of catecholamines via alpha2-adrenoreceptors in the progress of acute colitis, and suggest that use of the alpha2-adrenoceptor antagonist represents a novel therapeutic approach for the management of colitis.
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PMID:Modulation of inflammatory response via alpha2-adrenoceptor blockade in acute murine colitis. 1925 Feb 73

A regulated low level of nitric oxide (NO) production in the body is essential for maintaining homeostasis (neuroprotection, vasorelaxation, etc.), though certain pathophysiological conditions associated with inflammation involve de novo synthesis of inducible NO synthase (iNOS) in immune cells, including macrophages. A large body of evidence indicates that many inflammatory diseases, such as colitis and gastritis, as well as many types of cancer, occur through sustained and elevated activation of this particular enzyme. The biochemical process of iNOS protein expression is tightly regulated and complex, in which the endotoxin lipopolysaccharide selectively binds to toll-like receptor 4 and thereby activates its adaptor protein MyD88, which in turn targets downstream proteins such as IRAK and TRAF6. This leads to functional activation of key protein kinases, including IkB kinases and mitogen-activated protein kinases (MAPKs), such as p38 MAPK, JNK1/2, and ERK1/2, all of which are involved in activating key transcription factors, including nuclear factor-kappaB and activator protein-1. In addition, the production of proinflammatory cytokines such as interferon-gamma and interleukin-12 potentiates iNOS induction in autocrine fashions. Meanwhile, an LPS-stimulated p38 MAPK pathway plays a pivotal role in the stabilization of iNOS mRNA, which has the AU-rich element in its 3'-untranslated region, for rapid NO production. Thus, suppression and/or inhibition of the above-mentioned signaling molecules may have a great potential for the prevention and treatment of inflammation-associated carcinogenesis. In fact, there have been numerous reports of phytochemicals found capable of targeting NO production by unique mechanisms, including polyphenols, terpenoids, and others. This review article briefly highlights the molecular mechanisms underlying endotoxin-induced iNOS expression in macrophages, and also focuses on promising natural agents that may be useful for anti-inflammation and anticarcinogenesis strategies.
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PMID:Chemoprevention with phytochemicals targeting inducible nitric oxide synthase. 1936 23

Helicobacter spp. represent a proportionately small but significant component of the normal intestinal microflora of animal hosts. Several of these intestinal Helicobacter spp. are known to induce colitis in mouse models, yet the mechanisms by which these bacteria induce intestinal inflammation are poorly understood. To address this question, we performed in vitro co-culture experiments with mouse and human epithelial cell lines stimulated with a selection of Helicobacter spp., including known pathogenic species as well as ones for which the pathogenic potential is less clear. Strikingly, a member of the normal microflora of rodents, Helicobacter muridarum, was found to be a particularly strong inducer of CXC chemokine (Cxcl1/KC, Cxcl2/MIP-2) responses in a murine intestinal epithelial cell line. Time-course studies revealed a biphasic pattern of chemokine responses in these cells, with H. muridarum lipopolysaccharide (LPS) mediating early (24-48 h) responses and live bacteria seeming to provoke later (48-72 h) responses. H. muridarum LPS per se was shown to induce CXC chemokine production in HEK293 cells stably expressing Toll-like receptor 2 (TLR2), but not in those expressing TLR4. In contrast, live H. muridarum bacteria were able to induce NF-kappaB reporter activity and CXC chemokine responses in TLR2-deficient HEK293 and in AGS epithelial cells. These responses were attenuated by transient transfection with a dominant negative construct to NOD1, and by stable expression of NOD1 siRNA, respectively. Thus, the data suggest that both TLR2 and NOD1 may be involved in innate immune sensing of H. muridarum by epithelial cells. This work identifies H. muridarum as a commensal bacterium with pathogenic potential and underscores the potential roles of ill-defined members of the normal flora in the initiation of inflammation in animal hosts. We suggest that H. muridarum may act as a confounding factor in colitis model studies in rodents.
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PMID:A commensal Helicobacter sp. of the rodent intestinal flora activates TLR2 and NOD1 responses in epithelial cells. 1940 79


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