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)

We studied the release of tumor necrosis factor-alpha (TNF alpha), a vital immunoregulatory cytokine, by alveolar macrophages (M phi s) infected with simian immunodeficiency virus (SIV) in vitro or collected from SIV-infected macaques. For in vitro studies, M phi s were harvested by bronchoalveolar lavage from 5 normal animals and infected in flasks with SIV (10(4)TCID50/2.5 x 10(6) M phi s). After 7 to 10 days, cytopathic effect was prominent and 68 +/- 2% of M phi s were immunoreactive for p27 core protein. Uninfected (control) and SIV-infected M phi s were then cultured for 24 hours in 96-well plates (10(5) M phi s/well) while challenged with lipopolysaccharide (LPS; 100 micrograms/ml). TNF alpha was assayed in culture supernatants by an enzyme-linked immunosorbent assay (detection limit, 50 pg/ml) and results were expressed as pg TNF alpha/ml/10(3) M phi s (mean +/- SEM). TNF alpha was not detected in unstimulated wells. TNF alpha release by control and SIV-infected M phi s was similar (6.6 +/- 0.7 and 7.9 +/- 1.1 pg/ml/10(3) M phi s, respectively). We also studied TNF alpha release by alveolar M phi s from 8 animals infected with SIV (3 asymptomatic, 5 with acquired immune deficiency syndrome virus (AIDS]. One animal with AIDS had p27+ M phi s. Alveolar M phi s from asymptomatic animals released significantly more TNF alpha (10.3 +/- 1.1 pg/ml/10(3) M phi s) than did animals with AIDS or uninfected macaques (5.2 +/- 0.8 and 7.0 +/- 0.6 pg/ml/10(3) M phi s, respectively) (p less than 0.01). However, M phi s from monkeys with AIDS failed to respond to LPS after 7 to 10 days in culture. In summary, in vitro infection with SIV does not cause constitutive TNF alpha release or alter the response of cultured M phi s to LPS. When kept in culture, M phi s collected from asymptomatic, SIV-infected animals retain their response to LPS, whereas M phi s from animals with AIDS lose the capacity to produce TNF alpha. Furthermore, M phi s cytokine production is exaggerated before overt clinical disease, but not as a direct result of infection with SIV.
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PMID:Effect of simian immunodeficiency virus infection on tumor necrosis factor-alpha production by alveolar macrophages. 189 Aug 5

To study proteoglycan metabolism in inflammatory macrophages, primary cultures of human macrophages were cultured in the absence and presence of bacterial lipopolysaccharide (LPS). When exposed to [35S]sulfate, the cells incorporated the label almost exclusively into chondroitin sulfate proteoglycan (CSPG), which was recovered from the culture medium and the cell layer. Cells stimulated with LPS secreted approximately three times more [35]CSPG into the culture medium than control cells. Furthermore, cell adhesion was also found to promote proteoglycan secretion; when nonadherent monocytic cells were induced to adhere, the release of proteoglycan increased two times. The increased secretion seen in LPS-stimulated macrophages was partly due to increased biosynthesis, but was mostly due to increased sorting of CSPG to the secretory pathway. Only about 20% of the CSPG synthesized in unstimulated cells was secreted, whereas the corresponding figure in LPS-treated cells was 35%. In both cell types, the remaining [35S]CSPG was degraded, probably in the lysosomes. The degradation was a two-step process. First, the [35S]CSPG was rapidly cleaved to yield free glycosaminoglycan (GAG) chains (t1/2 = 15 to 30 minutes). Secondly, the GAG chains were completely depolymerized (t1/2 = 2 to 3 hours). Neither resting nor LPS-stimulated cells sorted CSPG to intracellular storage, as is evident in many hematopoietic cells. The LPS-treated cells synthesized [35S]CSPG of smaller molecular size than did control cells, with GAG chains of approximate molecular mass of 12 kD versus 16 kD in control cells. No difference was seen in the disaccharide composition of the GAG chains; both LPS-stimulated and unstimulated cells expressed a mixture of 80% to 90% chondroitin 4-sulfate and 10% to 20% chondroitin 4,6-disulfate. N-terminal sequence and Northern blot analysis indicate that the core protein of the CSPG secreted by human macrophages is serglycin.
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PMID:Proteoglycan metabolism in normal and inflammatory human macrophages. 821 36

The production of tumor necrosis factor alpha (TNF-alpha), a key proinflammatory cytokine essential for the function of the immune system, is regulated at both the transcriptional and posttranscriptional levels. In this report, we focus on the interaction of TNF-alpha mRNA with macrophage proteins, likely mediators of its post-transcriptional control. Mapping of murine TNF-alpha mRNA by using a combination of RNase protection and RNA gel shift assays revealed that two distinct sites within the 3' untranslated region (3'-UTR) engage in the formation of four major RNA-protein complexes, while no protein binding to the 5'-UTR or coding sequences was detected. The protein-binding site of three RNA-protein complexes, A, B, and C, is positioned between bases 1291 and 1320 inside the AU-rich sequence, a region previously shown to be crucial for both translational repression and lipopolysaccharide inducibility of TNF-alpha. An additional protein complex (complex D) whose binding to the TNF-alpha 3'-UTR was independent of the presence of AU-rich sequences was identified. At least six protein species with apparent molecular masses of 48, 52, 54, 81, 101, and 150 kDa are in direct contact with TNF-alpha mRNA. The RNA-binding proteins are differentially distributed in the cell: complexes A and D are present predominantly in the cytosol, while complexes B and C are found in the nucleus and associated with particulate cytoplasmic fractions. Cytosolic complex A displays comparatively high specificity for TNF-alpha mRNA, while the binding of complexes B and C to TNF-alpha mRNA is readily competed for by other AU-rich sequence-containing RNAs. In summary, these findings demonstrate that two regions of the TNF-alpha mRNA molecule interact with macrophage RNA-binding protein complexes that differ in their core protein composition, cellular distribution, and affinity to TNF-alpha mRNA.
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PMID:Two distinct regions in the 3' untranslated region of tumor necrosis factor alpha mRNA form complexes with macrophage proteins. 881 70

Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Following intraperitoneal injection of lipopolysaccharide (LPS), syndecan-4-deficient mice exhibited high mortality compared with wild-type controls. Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1beta was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1beta was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor-beta1 was impaired in the syndecan-4-deficient macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of transforming growth factor-beta1 on IL-1beta production.
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PMID:Syndecan-4 deficiency leads to high mortality of lipopolysaccharide-injected mice. 1158 25

Hepatitis C virus (HCV) is remarkably efficient at establishing chronic infection. One of the reasons for this appears to be the suppression of the accessory cell function of professional antigen presenting cells. In the present study, the immunosuppressive activity of HCV protein was examined on dendritic cells (DCs) generated from mouse bone marrow progenitor cells in vitro. We found that the DCs forced to express HCV protein have defective allostimulatory ability. DCs expressing HCV protein were phenotypically indistinguishable from normal DCs. However, they were unable to produce IL-12 effectively when stimulated with lipopolysaccharide. The functional domain of the HCV protein essential for immunosuppression was determined using a series of NH2-and C-terminal deletion mutants of HCV core protein. We found that amino acid residues residing between the 21st and the 40th residues from the NH2-terminus of HCV core protein are required for immunosuppression. These findings suggest that HCV core protein suppresses the elicitation of protective Th1 responses by the inhibition of IL-12 production by DCs.
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PMID:Identification of hepatitis C virus core domain inducing suppression of allostimulatory capacity of dendritic cells. 1213 11

Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Syndecan-4-deficient [(Synd4(-/-)] mice were produced to clarify the in vivo role of syndecan-4. Synd4(-/-) mice were more susceptible to kappa-carrageenan-induced nephropathy, and the placental labyrinth from the deficient embryos exhibited more thrombi than wild-type ones. Importantly, Synd4(-/-) mice were more susceptible to endotoxin shock. Further analysis revealed that the mechanism to suppress excessive production of interleukin-1beta (1L-1beta) by transforming growth factor-beta (TGF-beta) was impaired in the deficient mice. TGF-beta, one of the cytokines involved in the suppression mechanism, bound to heparan sulfate chain of syndecan-4, which was induced in macrophages and the microvasculature after administration of lipopolysaccharide. Therefore, augmentation of TGF-beta function by induced syndecan-4 was suggested as a mechanism of the suppressive action of syndecan-4 against endotoxin shock.
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PMID:Syndecan-4 as a molecule involved in defense mechanisms. 1297 10

Hepatitis C virus (HCV) is remarkably efficient at establishing persistent infection, suggesting that it has evolved one or more strategies aimed at evading the host immune response. T cell responses, including interferon-gamma production, are severely suppressed in chronic HCV patients. The HCV core protein has been previously shown to circulate in the bloodstream of HCV-infected patients and inhibit host immunity through an interaction with gC1qR. To determine the role of the HCV core-gC1qR interaction in modulation of inflammatory cytokine production, we examined interleukin (IL)-12 production, which is critical for the induction of interferon-gamma synthesis, in lipopolysaccharide-stimulated human monocyte/macrophages. We found that core protein binds the gC1qR displayed on the cell surface of monocyte/macrophages and inhibits the production of IL-12p70 upon lipopolysaccharide stimulation. This inhibition was found to be selective in that HCV core failed to affect the production of IL-6, IL-8, IL-1beta, and tumor necrosis factor alpha. In addition, suppression of IL-12 production by core protein occurred at the transcriptional level by inhibition of IL-12p40 mRNA synthesis. Importantly, core-induced inhibition of IL-12p40 mRNA synthesis resulted from impaired activation of AP-1 rather than enhanced IL-10 production. These results suggest that the HCV core-gC1qR interaction may play a pivotal role in establishing persistent infection by dampening TH1 responses.
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PMID:Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. 1529 84

Dendritic cells (DCs) need to mobilize within the extracellular matrix (ECM) during their maturation and concomitant migration from peripheral sites to lymphoid organs. Syndecans are cell surface proteoglycans that mediate the interaction of DCs with the ECM. Here we investigated the influence of syndecans on dendritic cell motility and morphology. Langerhans cells of the epidermis and monocyte-derived DCs were found to undergo a switch in syndecan expression during maturation. Syndecan-1 was downregulated and syndecan-4 was strongly upregulated within the first hours of lipopolysaccharide-induced dendritic cell maturation and during Langerhans cell emigration from human skin, as shown by flow cytometry and qRT-PCR. Syndecan-1 downregulation was inhibited by syndecan-4 siRNA knock-down, indicating a functional interconnection between enhanced syndecan-4 expression and syndecan-1 downregulation. Syndecan-4 upregulation is functionally involved in dendritic cell motility, as inhibition of syndecan-4 function by means of blocking antibodies or through siRNA knock-down decreased dendritic cell motility. In other experiments, the cytoskeletal component a-actinin was observed to be upregulated in DCs as a consequence of the induction of maturation, and was found to colocalize with syndecan-4. Furthermore, lammellopodial spreading by DCs on fibronectin (FN)-coated surfaces was dependent on syndecan-4. This binding of syndecan-4 to FN and its association with the cytoskeleton may be relevant for syndecan-4-dependent dendritic cell motility. We conclude that the switch in syndecan expression during dendritic cell maturation controls the motility of DCs in a way that appears to be crucial for their mobilization from peripheral sites and subsequent migration to lymphoid tissues.
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PMID:Switch in syndecan-1 and syndecan-4 expression controls maturation associated dendritic cell motility. 1757 38

Lumican is an extracellular matrix protein modified as a proteoglycan in some tissues. The core protein with leucine-rich repeats, characteristic of the leucine-rich-repeat superfamily, binds collagen fibrils and regulates its structure. In addition, we believe that lumican sequestered in the pericellular matrix interacts with cell surface proteins for specific cellular functions. Here we show that bacterial lipopolysaccharide sensing by the Toll-like receptor 4 signaling pathway and innate immune response is regulated by lumican. Primary cultures of lumican-deficient (Lum(-/-)) macrophages show impaired innate immune response to lipopolysaccharides with lower induction of tumor necrosis factor alpha (TNFalpha) and interleukin-6. Macrophage response to other pathogen-associated molecular patterns is not adversely affected by lumican deficiency, suggesting a specific role for the lumican core protein in the Toll-like receptor 4 pathway. An exogenous recombinant lumican core protein increases lipopolysaccharide-mediated TNFalpha induction and partially rescues innate immune response in Lum(-/-) macrophages. We further show that the core protein binds lipopolysaccharide. Immunoprecipitation of lumican from peritoneal lavage co-precipitates CD14, a cell surface lipopolysaccharide-binding protein that is involved in its presentation to Toll-like receptor 4. The Lum(-/-) mice are hypo-responsive to lipopolysaccharide-induced septic shock, with poor induction of pro-inflammatory cytokines, TNFalpha, and interleukins 1beta and 6 in the serum. Taken together, the data indicates a novel role for lumican in the presentation of bacterial lipopolysaccharide to CD14 and host response to this bacterial endotoxin.
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PMID:A novel role of the lumican core protein in bacterial lipopolysaccharide-induced innate immune response. 1761 30

We previously reported that LDL modified by group V secretory phospholipase A2 (GV-LDL) promotes macrophage foam cell formation through a mechanism independent of scavenger receptors SR-A and CD36, and dependent on cellular proteoglycans. This study investigates the role of syndecans, a family of cell surface proteoglycans known to mediate endocytosis through macropinocytosis, in macrophage uptake of GV-LDL. LY 294002, a phosphatidylinositol 3-kinase inhibitor, significantly reduced internalization of (125)I-labeled GV-LDL in J-774 macrophages, consistent with a macropinocytic uptake pathway. Using small, interfering RNA-directed gene silencing, we demonstrated a direct relationship between (125)I-labeled GV-LDL binding and the level of syndecan-3 and syndecan-4 expression in J-774 cells. However, (125)I-labeled GV-LDL uptake was significantly reduced only when syndecan-4 expression was suppressed. Peritoneal macrophages from syndecan-4-deficient mice exhibited markedly reduced uptake of fluorescently labeled GV-LDL compared with wild-type cells. Furthermore, cholesteryl ester accumulation induced by GV-LDL was dependent on syndecan-4 expression. Syndecan-4 expression and GV-LDL binding were significantly increased in J-774 cells treated with lipopolysaccharide, suggesting that GV-LDL uptake via this pathway may be enhanced during inflammation. Taken together, our data point to a novel role for syndecan-4 in mediating the uptake of GV-LDL, a process implicated in atherosclerotic lesion progression.
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PMID:Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified LDL. 1905 5


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