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)

Interleukin-1 and tumor necrosis factor-alpha are potent, multifunctional cytokine mediators of inflammation and immune responses that are produced primarily by activated monocytes and macrophages. Three published papers by different groups have shown that heat shock and chemical stress with heavy metal salts or sulfhydryl reagents, all of which induce the expression of heat shock protein 70 (hsp70), concomitantly inhibit the production of these cytokines in human monocytes and mouse macrophages activated by lipopolysaccharide. These papers are reviewed and discussed in some detail. Other studies suggest that various anti-inflammatory drugs, including acetylsalicyclic acid, auranofin and dexamethasone, can also facilitate HSP expression in macrophages. However, while these studies are interesting, it is clear that not a great deal of work has been done and/or published in this area. Since many pharmaceutical companies are developing cytokine synthesis inhibitors as potential anti-inflammatory drugs, one aim of this article is to emphasize that understanding the molecular mechanism(s) that lead to increased HSP expression and decreased cytokine biosynthesis may assist in achieving this goal.
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PMID:Role of hsp70 in cytokine production. 798 64

Smooth Brucella spp. share certain lipopolysaccharide antigens with other bacteria, resulting in serological cross-reactions which can prevent the definitive diagnosis of brucellosis. To identify other antigens with serodiagnostic potential, immunoblot studies following sodium dodecyl sulphate-polyacrylamide gel electrophoresis were carried out. Sera from pigs experimentally infected with Brucella suis and naturally infected feral pigs, sera from pigs from a farm with a known history of Yersinia enterocolitica 0:9 infection, Brucella Complement Fixation Test (CFT) reactor pigs (aetiology unknown) and pigs from consistently Brucella CFT negative farms were examined. Although B. suis infected pigs recognized a total of nine B. melitensis antigens, individual pigs rarely recognized more than three antigens in the range. A 62 kDa antigen was recognized by the majority (73%) of the Brucella infected pigs, but only by 10 to 23% of pigs from the other groups. This antigen was shown to be the Brucella homologue of the ubiquitous 65 kDa heat shock protein (HSP-65) family by immunoblot studies with 14 monoclonal antibodies to the Mycobacterium leprae HSP-65. Only four of these monoclones (Y1.2, ML-30, D7C and IIIC8) identified the B. melitensis 62 kDa protein suggesting that unshared, potentially Brucella specific, regions exist. Sera from Y. enterocolitica 0:9 infected pigs, CFT reactor pigs (aetiology unknown), CFT negative pigs and hyperimmune pig serum raised to Y. enterocolitica 0:9 also recognized B. melitensis antigens, most notably a 17 kDa protein. This antigen appears to be a common cross-reactive protein.
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PMID:Immunoblot studies in the differential diagnosis of porcine brucellosis: an immunodominant 62 kDa protein is related to the mycobacterial 65 kDa heat shock protein (HSP-65). 820 27

We recently reported that lipopolysaccharide (LPS) induces apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC). Information about survival signals against this and other stimuli for endothelial cell apoptosis is limited to factors in the extracellular space. In other cell types, apoptosis is also affected by intracellular gene products. The heat-shock response is a highly conserved cellular stress response affording cytoprotection against a variety of cytotoxic conditions. Accordingly, we tested the hypothesis that prior induction of the heat-shock response would affect apoptosis in cultured SPAEC. Exposure of SPAEC to either heat (43 degrees C, 90 min) or sodium arsenite (100 microM, 90 min) induced expression of heat-shock protein-70 (HSP-70). LPS (0.1 microg/ml) treatment of SPAEC induced apoptotic morphology, cell detachment, high molecular weight (> 30 kb) DNA fragmentation, and internucleosomal DNA fragmentation. Prior induction of the heat-shock response attenuated LPS-mediated apoptosis, a protective event associated with a concomitant attenuation of rapid (within minutes) LPS-stimulated superoxide anion (O2.-) generation. Subsequent experiments involving transient overexpression of HSP-70, by direct gene transfer, suggest a direct role for HSP-70 in the attenuation of LPS-mediated apoptosis. We conclude that the heat-shock response is an intracellular survival signal against LPS-mediated apoptosis, and that the protective mechanism may involve HSP-70 directly, as well as inhibition of LPS-mediated O2.- generation.
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PMID:The heat-shock response attenuates lipopolysaccharide-mediated apoptosis in cultured sheep pulmonary artery endothelial cells. 896 69

Both chlamydial and human heat shock protein 60s (HSP 60), which colocalize in human atheroma, may contribute to inflammation during atherogenesis. We tested the hypothesis that chlamydial or human HSP 60 activates human endothelial cells (ECs), smooth muscle cells (SMCs), and monocyte-derived macrophages. We examined the expression of adhesion molecules such as endothelial-leukocyte adhesion molecule-1 (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), and the production of the proinflammatory cytokine interleukin-6 (IL-6). We also tested whether either HSP 60 induces nuclear factor-kappaB (NF-kappaB), which contributes to the gene expression of these molecules. Either chlamydial or human HSP 60 induced E-selectin, ICAM-1, and VCAM-1 expression on ECs similar to levels induced by Escherichia coli lipopolysaccharide (LPS). Each HSP 60 also significantly induced IL-6 production by ECs, SMCs, and macrophages to an extent similar to that induced by E. coli LPS, as assessed by enzyme-linked immunosorbent assay (ELISA). In ECs, either HSP 60 triggered activation of NF-kappaB complexes containing p65 and p50 Rel proteins. Heat treatment abolished all these effects, but did not alter the ability of E. coli LPS to induce these functions. Chlamydial and human HSP 60s therefore activate human vascular cell functions relevant to atherogenesis and lesional complications. These findings help to elucidate the mechanisms by which a chronic asymptomatic chlamydial infection might contribute to the pathophysiology of atheroma.
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PMID:Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. 1002 66

Recent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic form to a nuclear, DNA binding state. As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c- fos, we have examined the potential role of HSF1 in the effects of NSAIDs on gene expression in a human monocytic cell line THP-1. We found that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression. In addition, sodium salicylate and additional NSAIDs used at concentrations that activate HSF1 also inhibited the expression of other monocytic genes (TNF-alpha, IL-1beta, IL-6, IL-8, IL-10, ICAM-1) activated by exposure to a pro-inflammatory stimulus (lipopolysaccharide, LPS). At least in the case of the IL1B promoter, repression did not seem to involve another factor whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically to HSF1. Exposure to NSAIDs had a complex effect on HSP gene expression and while sulindac activated the stress responsive HSP70B promoter, sodium salicylate did not. In addition, only a subset of the NSAIDs induced HSP70 mRNA species. These findings reflect the properties of HSF1 which can be activated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differentially induce one or other of these forms. Overall therefore, exposure to NSAIDs leads to a profound switch in gene expression in monocytic cells, with suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects.
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PMID:Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. 1032 74

The methanolic extract from the leaves of Laurus nobilis (bay leaf, laurel) was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Through bioassay-guided separation, fourteen known sesquiterpenes were isolated from the active fraction and were examined for ability to inhibit the NO production. Seven sesquiterpene lactones (costunolide, dehydrocostus lactone, eremanthine, zaluzanin C, magnolialide, santamarine and spirafolide) potently inhibited LPS-induced NO production (IC50 = 1.2 approximately 3.8 microM). Other sesquiterpene constituents also showed the inhibitory activity (IC50 > or = 21 microM), but their inhibitory activities were less than those of sesquiterpene lactones. Alpha-methylene-gamma-butyrolactone also showed inhibitory activity (IC50 = 9.6 microM), while mokko lactone and watsonol A etc., reductants of the alpha-methylene-gamma-butyrolactone moiety by NaBH4 or DIBAL, and a 2-mercaptoethanol adduct of dehydrocostus lactone showed little activity (IC50 > or = 18 microM). These results indicated that the alpha-methylene-gamma-butyrolactone moiety is important for the activity. Furthermore, costunolide and dehydrocostus lactone inhibited inducible nitric oxide synthase (iNOS) induction in accordance with induction of heat shock protein 72 (HSP 72). These results suggested that, as one of their mechanisms of action, sesquiterpene lactones induce HSP 72 thereby preventing nuclear factor-kappaB activation followed by iNOS induction.
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PMID:Inhibitory effects of sesquiterpenes from bay leaf on nitric oxide production in lipopolysaccharide-activated macrophages: structure requirement and role of heat shock protein induction. 1083 99

Immune function is markedly attenuated in endotoxemia. Zinc is involved in the regulation of cellular functions and maintenance of immune function, and its level in the serum is low in endotoxemia. We mainly investigated the effects of zinc acetate (ZA) on splenocytes in mice with endotoxemia. After we confirmed increased plasma zinc level by ZA treatment, C57BL/6 mice were randomly divided into four groups: 10 control mice received 500 microL saline solution as vehicle; 10 control mice received ZA at 3 mg/kg body weight; 20 endotoxemic mice received a 40 mg/kg lethal dose of lipopolysaccharide (LPS); 20 mice received ZA followed by LPS as the above dose. In vivo, we confirmed that ZA pretreatment did not significantly affect the plasma cytokine level in endotoxemic mice. In vitro, splenocytes from ZA-plus-LPS mice showed drastic effects, in that ZA abrogated LPS-induced suppression of cellular proliferation and production of interleukin-2 and interferon-gamma. The percentage of apoptotic splenocytes was significantly reduced in ZA-plus-LPS mice (23.4%) as compared with LPS mice (41.6%). Furthermore, the expression of HSP-70 mRNA in splenocytes was strongly enhanced in both ZA and ZA-plus-LPS mice, especially in the latter group. Finally, studies monitoring survival rates for 6 days showed that LPS caused 100% mortality while ZA-plus-LPS mice showed 75% survival. Our results suggest that zinc normalized the immune response and reduced apoptosis of splenocytes. These changes were probably caused by increased synthesis of HSP-70 by splenocytes, which might enhance survival of mice with LPS-induced endotoxemia.
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PMID:Effects of zinc acetate on splenocytes of endotoxemic mice: enhanced immune response, reduced apoptosis, and increased expression of heat shock protein 70. 1115 21

The heat shock response protects against sepsis-induced mortality, organ injury, cardiovascular dysfunction, and apoptosis. Several inducers of the heat shock response, such as hyperthermia, sodium arsenite, and pyrollidine dithiocarbonate, inhibit NF-kappaB activation and nitric oxide formation. The antioxidant lipoic acid (LA) has recently been found to inhibit NF-kappaB activation and nitric oxide formation. We therefore tested the hypothesis that LA induces a heat shock response. To test this hypothesis, we determined whether exposure to LA affects expression of both heat shock protein 70 (HSP-70) and nuclear heat shock factor-1 (HSF-1) in lipopolysaccharide (LPS) stimulated macrophages. LA and hyperthermia attenuated LPS-induced increases in nuclear NF-kappaB, iNOS protein, and media nitrite concentrations. LPS and hyperthermia increased HSP-70 concentrations 8-fold and 20-fold, respectively. No effect of LA treatment alone on HSP-70 protein expression was detected. Likewise, no effect of LA on HSF-1 protein expression was detected. These data suggest that LA inhibits LPS-induced activation of iNOS in macrophages independent of the heat shock response.
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PMID:alpha-lipoic acid inhibits endotoxin-stimulated expression of iNOS and nitric oxide independent of the heat shock response in RAW 264.7 cells. 1545 32

We investigated whether an acyclic polyisoprenoid antiulcer drug, geranylgeranylacetone (GGA), induces the expression of HSP70 in the rat cochlea. Immunoblotting revealed upregulation of HSP70 in the cochlea at 12 h after transtympanic (local) or oral (systemic) administration of GGA, and this increased at 24 h after administration. Positive immunohistochemical staining of HSP70 was observed in the hair cells, the spiral ganglion, the stria vascularis, the spiral ligament, and the perivascular portion of modiolar vessels. We therefore subsequently studied the effects of GGA as an HSP-inducer on inner ear trauma due to inflammation. Damage to the lateral wall due to inflammation induced by lipopolysaccharide inoculation was protected against by pretreatment with GGA, as assessed physiologically by measurement of cochlear blood flow and morphologically by electron microscopy. The results of the present study suggest that GGA can protect the cochlea against other injuries including those induced by noise, ototoxic drugs, and ischemia by upregulating HSP70.
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PMID:Upregulation of HSP by geranylgeranylacetone protects the cochlear lateral wall from endotoxin-induced inflammation. 1592 99

The regimen of estrogen replacement can alter the consequences of estrogen therapy and stressors. To determine the long-term effects and interaction of these systems on the brain and periphery, adult female rats were infused with lipopolysaccharide (LPS) into the fourth ventricle of the brain for 4 weeks, and ovariectomized rats were administered either constant or pulsed regimens of estrogen replacement (17beta-estradiol) until sacrifice at 8 weeks. Constant, but not pulsed, estrogen replacement reduced ERalpha and increased HSP90, HSP70, and PR(B) uterine protein levels. Both estrogen regimens increased ERbeta, HSP27, and PR(A) uterine proteins. Both regimens reduced hypothalamic levels of ERalpha, but not ERbeta, HSP, or PR. No changes were observed in the hippocampus. Long-term brain infusion of LPS activated microglia and reduced body weight, but did not alter corticosterone or nitrotyrosine levels. LPS infusion into intact rats suppressed uterine weight, increased ERalpha and decreased HSP90 in the uterus. LPS did not alter uterine weight in ovariectomized rats treated with constant or pulsed estrogen. Together, these data suggest the timing of estrogen replacement and neuroinflammatory stressors can profoundly affect uterine and hypothalamic steroid receptor expression and may be important parameters to consider in the post-menopausal intervention with estrogen.
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PMID:Estrogen replacement regimen and brain infusion of lipopolysaccharide differentially alter steroid receptor expression in the uterus and hypothalamus. 1824 62


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