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)

Expression of heat shock proteins (HSP) is an adaptive response to cellular stress. Stress induces tumor necrosis factor (TNF)-alpha production. In turn, TNF-alpha induces HSP70 expression. However, osmotic stress or ultraviolet radiation activates TNF-alpha receptor I (TNFR-I) in the absence of TNF-alpha. We postulated that TNF-alpha receptors are involved in the induction of HSP70 by cellular stress. Peritoneal Mphi were isolated from wild-type (WT), TNF-alpha knockout (KO), and TNFR (I or II) KO mice. Cells were cultured overnight and then heat stressed at 43 +/- 0.5 degrees C for 30 min followed by a 4-h recovery at 37 degrees C. Cellular HSP70 expression was induced by heat stress or exposure to endotoxin [lipopolysaccharide (LPS)] as determined by immunoblotting. HSP70 expression induced by either heat or LPS was markedly decreased in TNFR-I KO Mphi, whereas TNFR-II KO Mphi exhibited HSP70 expression comparable to that in WT mice. Expression of HSP70 after heat stress in TNF-alpha KO Mphi was also similar to that in WT mice, suggesting that induction of HSP70 by TNFR-I occurs independently of TNF-alpha. In addition, levels of steady-state HSP70 mRNA were similar by RT-PCR in WT and TNFR-I KO Mphi despite differences in protein expression. Furthermore, the effect of TNFR-I appears to be cell specific, since HSP70 expression in splenocytes isolated from TNFR-I KO was similar to that in WT splenocytes. These studies demonstrate that TNFR-I is required for the synthesis of HSP70 in stressed Mphi by a TNF-independent mechanism and support an intracellular role for TNFR-I.
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PMID:TNF receptor I is required for induction of macrophage heat shock protein 70. 1140 47

The effect of bacterial lipopolysaccharide (LPS) on the expression of mRNA encoding heme oxygenase-1 (HO-1), which is the rate limiting enzyme in heme catabolism and is also known as heat shock protein 32 (HSP32), was examined in primarily cultured rat glial cells. Treatment of cells with LPS elicited an increase in HO-1 mRNA, accompanying down regulation of delta-aminolevulinate synthase, in a dose-dependent fashion. HO-1 mRNA increased markedly at 12 h after LPS treatment (10 microg/ml) and reached a maximum at 24 h. In contrast, HSP70, a major heat shock protein, slightly increased only at 6 h after LPS treatment and returned to the control level by 12 h. These results suggest that HSPs are induced under separate regulation during glial activation by LPS through oxidative stress, a part of which is likely mediated by intracellular free heme.
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PMID:Gene expression of heme oxygenase-1 during glial activation by lipopolysaccharide. 1148 74

Although CD14 has been implicated in the immune recognition of bacterial lipopolysaccharide (LPS) from Gram-negative bacteria and also peptidoglycan (PGN) and lipoteichoic acid (LTA) from the outer cell wall of Gram-positive bacteria, accumulating evidence has suggested the possible existence of other functional receptor(s). In this study, we have used fluorescence recovery after photobleaching (FRAP) in order to get the first dynamic picture of the innate recognition of bacteria. We have found that the diffusion coefficient of CD14 remains unaffected after LPS ligation and that the diffusion coefficients of FITC-LPS and FITC-LTA bound to cells differ from that of CD14. Furthermore, FITC-LPS/LTA rapidly become immobile when bound to cells, suggesting that FITC-LPS/LTA must briefly associate with CD14 in the initial attachment process and rapidly move on to an immobile receptor or to a complex of receptors. Further FRAP experiments revealed that heat shock protein 70 (hsp70) and hsp90 are immobile in cell membranes, and antibodies against them were found to block the transfer of LPS to the immobile receptor and to inhibit interleukin 6 production upon LPS stimulation. These experiments indicated that LPS transfers from CD14 to hsp70 and hsp90, which may be part of an LPS/LTA multimeric receptor complex. Thus, hsps are implicated as mediators of the innate activation by bacteria.
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PMID:Fluorescence recovery after photobleaching reveals that LPS rapidly transfers from CD14 to hsp70 and hsp90 on the cell membrane. 1155 61

Using commercially available recombinant human heat shock protein 70 (rhHsp70), recent studies have shown that rhHsp70 could induce the production of tumor necrosis factor alpha (TNFalpha) by macrophages and monocytes in a manner similar to lipopolysaccharide (LPS) e.g. via CD14 and Toll-like receptor 4-mediated signal transduction pathway. In the current study, we demonstrated that a highly purified rhHsp70 preparation (designated as rhHsp70-1) with a LPS content of 1.4 pg/microg was unable to induce TNFalpha release by RAW264.7 murine macrophages at concentrations up to 5 microg/ml. In contrast, a less purified rhHsp70 preparation (designated as rhHsp70-2) at 1 microg/ml with a LPS content of 0.2 ng/microg was able to induce TNFalpha release to the same extent as that induced by 0.2 ng/ml LPS. Failure of rhHsp70-1 to induce TNFalpha release was not because of defective physical properties since rhHsp70-1 and rhHsp70-2 contained identical hsp70 content as determined by SDS gels stained with Coomassie Blue and Western blots probed with an anti-rhHsp70 antibody. Both rhHsp70 preparations also had similar enzymatic activities as judged by their ability to remove clathrin from clathrin-coated vesicles. Removal of LPS from rhHsp70-2 by polymyxin B-agarose column or direct addition of polymyxin B to the incubation medium essentially eliminated the TNFalpha-inducing activity of rhHsp70-2. The addition of LPS at the concentration found in rhHsp70-2 to rhHsp70-1 resulted in the same TNFalpha-inducing activity as observed with rhHsp70-2. The TNFalpha-inducing activities of rhHsp-2, LPS alone, and LPS plus rhHsp70-1 were all equally sensitive to heat inactivation. These results suggest that rhHsp-70 does not induce TNFalpha release from murine macrophages and that the observed TNFalpha-inducing activity in the rhHsp70-2 preparation is entirely due to the contaminating LPS.
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PMID:Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor alpha release by murine macrophages. 1240 78

The effect of multiple lipopolysaccharide (LPS) challenges in swine undergoing long-term treatment with porcine somatotropin (PST) was determined. Changes in aspartate serine transaminase (AST) occurred only at 24h following the first LPS challenge dose (P<0.05), while PST treatment moderated any change from occurring. Nonesterified free fatty acid (NEFA) levels were elevated in PST treated animals for the first 3 days following daily LPS treatment (P<0.05), while LPS treatment alone had no effect on plasma NEFA levels. Plasma urea nitrogen (PUN) levels were unchanged by LPS following the initial LPS challenge, but were decreased following the second challenge dose (P=0.014). These changes were long lasting, with a return to normal PUN levels not evident until Day 6. The PST treatment mitigated changes in PUN (P<0.05) when LPS was administered. Haptoglobin plasma levels, along with lipid peroxide production were not affected by LPS challenge or PST administration. LPS challenge reduced the levels of immunoreactive heat shock protein 70 (HSP70) throughout the entire challenge period (P<0.001). PST-LPS animals had normal levels of this protein. The results of the present study demonstrate that long-term PST treatment mitigates the adverse effects of subchronic LPS administration.
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PMID:Long-term recombinant porcine somatotropin (PST) treatment mitigates the responses to subchronic lipopolysaccharide in swine. 1258 15

We have investigated the role of Toxoplasma gondii-derived heat shock protein 70 (TgHSP70) as a B cell mitogen by measuring proliferative responses in vitro. TgHSP70 induced prominent proliferative responses in murine B cells derived not only from T gondii-infected but also from uninfected mice. Nude mice responded to TgHSP70; however, severe combined immunodeficiency, RAG1-/- B6, and microMT mice failed to respond. B220+ spleen cells showed marked proliferation after stimulation with TgHSP70, but neither CD4+ nor CD8+ population responded. This unresponsiveness of CD4+ and CD8- T cells to TgHSP70 was antigen presenting cells independent. These data indicate that TgHSP70 induced the proliferation of B cells but not T cells. Polymyxin B, a potent inhibitor of lipopolysaccharide (LPS), did not eliminate TgHSP70-induced proliferation. C3H/HeN mice responded well to TgHSP70 stimulation; however, C3H/HeJ mice carrying a point mutation in the Toll-like receptor (TLR) 4 failed to respond. This indicates that TLR4 is required for TgHSP70-induced B cell activation. The involvement of TLR4 in the TgHSP70-induced proliferative responses of spleen cells was also shown by the use of TLR4-/- mice. But TgHSP70-induced, but not LPS-induced, spleen cell proliferation was observed in MyD88-/- mice, indicating that the MyD88 molecule was involved in LPS-induced proliferation but not in TgHSP70-induced proliferation.
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PMID:Toxoplasma gondii-derived heat shock protein HSP70 functions as a B cell mitogen. 1265 80

We investigated the effects of aqueous extract from Platycodi radix (AEPR), a traditional drug used to treat acute lung inflammatory disease, on lipopolysaccharide (LPS)-induced inflammation in A549 human cultured airway epithelial cells. Nuclear factor-kappaB (NF-kappaB) and its inhibitory regulator, inhibitory kappaB (I-kappaB), play crucial roles in LPS-induced inflammatory response. We show that LPS-induced nuclear translocation of NF-kappaBp65 is inhibited by AEPR. LPS-induced expression of I-kappaBalpha, which is expressed by LPS-induced activation of NF-kappaB, is inhibited by AEPR as well. Besides LPS-induced expression of a group of genes, such as tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), are repressed by AEPR. We also found that expression of heat shock protein 70 (Hsp70), which has an anti-inflammatory activity, is increased by AEPR plus LPS. These results suggest that AEPR may act as a therapeutic agent for inflammatory disease through regulating the activity of NF-kappaB and expression of inflammatory genes.
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PMID:An aqueous extract of Platycodi radix inhibits LPS-induced NF-kappaB nuclear translocation in human cultured airway epithelial cells. 1513 22

The transition of dendritic cells (DCs) from immature to mature states is critical for the optimal priming of the adaptive immune response. This highly regulated process is accompanied by structural and functional alterations of DCs, including rapid and dramatic redistributions of MHC class I and class II molecules to cell surfaces, nuclear translocation of NF-kappaB,and transient appearance of dendritic cell aggresome-like induced structures (DALIS) in the cytosol. We have previously found that DCs can be matured by a non-inflammatory stress stimulation, i.e., heat shock. In this study, we examined if thermomanipulation could induce DALIS formation. We found that heat shock of DCs, but not of other cell types, led to the appearance of aggresome-like structures that were structurally indistinguishable from DALIS induced by lipopolysaccharide (LPS). Furthermore, the induction of DALIS in DCs by heat, but not by LPS, correlated with the increased ability of DCs to cross-present exogenous antigens to MHC I. Since the canonical biochemical response to heat shock is the induction of heat shock proteins (HSP) by heat shock factors (Hsf), we studied the contribution of both HSP and Hsf in heat shock-mediated DALIS formation using gene knockout mice. We demonstrated that neither inducible HSP70 nor the major mammalian heat shock transcription factor Hsf1 was involved in the formation of DALIS. Our results highlighted the important roles of heat shock in modulating the function of DCs, and they further suggested that heat-mediated immune regulation can be uncoupled from heat shock response.
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PMID:Heat shock-induced dendritic cell maturation is coupled by transient aggregation of ubiquitinated proteins independently of heat shock factor 1 or inducible heat shock protein 70. 1523 58

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

The CD40-CD154 system controls various aspects of the host inflammatory response in models of cellular and humoral immunity. Recently, we described a role for CD40 in the innate immune response in polymicrobial sepsis. However, recent data suggests that CD40 maybe activated by CD154 or directly via bacterial heat shock protein (HSP) 70. Therefore, we decided to test the mechanism of CD40 activation in murine polymicrobial sepsis. Wild-type (WT), CD40, and CD154 underwent cecal ligation and puncture (CLP). Compared with WT mice, CD40 had improved survival in association with attenuated production of IL-12, TNF-alpha, and IL-6. In contrast, CD154 mice behaved similar to WT mice with regard to mortality and cytokine production. The differential response of CD40 and CD154 mice to CLP was not due to a general attenuated response to inflammatory stimuli, as all three strains had similar survival after LPS administration, and CD40 macrophages had normal production of IL-12 in response to lipopolysaccharide. In contrast, CD40 macrophages had attenuated IL-12 production in response to Escherichia coli HSP70 (DnaK). Furthermore, intraperitoneal administration of DnaK resulted in a 4-fold increase in IL-12 in WT mice, which was absent in CD40 mice. This data demonstrates CD154-independent CD40 activation in polymicrobial sepsis and suggests that bacterial HSP70 is capable of stimulating CD40 in vitro and in vivo.
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PMID:Cd40 but not CD154 knockout mice have reduced inflammatory response in polymicrobial sepsis: a potential role for Escherichia coli heat shock protein 70 in CD40-mediated inflammation in vivo. 1554 25


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