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)

Alginate-poly-L-lysine (PLL) microcapsules can be used for transplantation of insulin-producing cells for treatment of type I diabetes. In this work we wanted to study the inflammatory reactions against implanted microcapsules due to PLL. We have seen that by reducing the PLL layer, less overgrowth of the capsule is obtained. By incubating different cell types with PLL and afterwards measuring cell viability with MTT, we found massive cell death at concentrations of PLL higher than 10 microg/ml. Staining with annexin V and propidium iodide showed that PLL induced necrosis but not apoptosis. The proinflammatory cytokine, tumor necrosis factor (TNF), was detected in supernatants from monocytes stimulated with PLL. The TNF response was partly inhibited with antibodies against CD14, which is a well-known receptor for lipopolysaccharide (LPS). Bactericidal permeability increasing protein (BPI) and a lipid A analogue (B-975), which both inhibit LPS, did not inhibit PLL from stimulating monocytes to TNF production. This indicates that PLL and LPS bind to different sites on monocytes, but because they both are inhibited by a p38 MAP kinase inhibitor, they seem to have a common element in the signal transducing pathway. These results suggest that PLL may provoke inflammatory responses either directly or indirectly through its necrosis-inducing abilities. By combining soluble PLL and alginate both the toxic and TNF-inducing effects of PLL were reduced. The implications of these data are to use alginate microcapsules with low amounts of PLL for transplantation purposes.
 ...
PMID:Poly-L-Lysine induces fibrosis on alginate microcapsules via the induction of cytokines. 1143 72

The general phosphodiesterase (PDE) inhibitor pentoxifylline (PTX), and the PDE type IV inhibitor rolipram (ROL), both increase intracellular cAMP levels and suppress inflammatory cytokine production by T cells and macrophages. We have previously shown that PTX and ROL protect from autoimmune diabetes in nonobese diabetic (NOD) mice. These drugs may mediate some of their anti-inflammatory effects by blocking nitric oxide (NO) production by macrophages. In this study, we investigated the effect of PDE inhibitors in blocking NO production by insulin-secreting NIT-1 insulinoma cells and mouse islet cells in vitro and in vivo. Insulinoma cells and islet cells produced NO when stimulated with a combination of inflammatory cytokines and lipopolysaccharide (LPS). We found that both PTX and ROL markedly suppressed this induced NO production. Islet cells express PDEs III and IV and, accordingly, the PDE III inhibitor cilostamide (CIL) also suppressed NO production, and a combination of ROL and CIL had a synergistic effect. This suppression appeared to be mediated, at least in part, by elevating cAMP level and was mimicked by other cAMP-elevating agents, ie, membrane-permeable cAMP analogs (dibutyryl cAMP and 8-bromo cAMP) and an adenylate cyclase stimulator (forskolin). PDE inhibitors suppressed the expression of inducible nitric oxide synthase (iNOS) mRNA. In vivo treatment with PTX or ROL prevented iNOS protein expression in the islets of NOD mice with cyclophosphamide-accelerated disease. Our findings suggest that PDE inhibitors can protect islets against autoimmunity.
 ...
PMID:Inhibitors of phosphodiesterase isoforms III or IV suppress islet-cell nitric oxide production. 1150 62

During infection/inflammation bacterial lipopolysaccharide (LPS) activates the immune system and thus enhances the level of circulating cytokines. These circulating cytokines induce adaptive processes within the endocrine system and in particular stimulate the HPA axis to increase the level of anti-inflammatory-acting glucocorticoids in the circulation. We have shown recently that LPS stimulates intrapituitary IL-6 production in folliculostellate cells via specific receptors and the p38a mitogen-activated protein kinase/nuclear factor-kappa B pathway. To test the physiological relevance of these findings, we studied whether LPS could enhance ACTH secretion via paracrine-acting intrapituitary IL-6. Lipopolysaccharide stimulated IL-6 secretion both in monolayer and aggregate mouse pituitary cell cultures, but only in aggregates, ACTH secretion was significantly enhanced by LPS. Other hormones, such as GH or PRL, were less stimulated by LPS. My4, an antibody that blocks the interaction of LPS with the LPS receptor CD14, suppressed both LPS-induced IL-6 and ACTH secretion in aggregate cultures. A neutralizing antibody against mouse IL-6 also inhibited LPS-induced ACTH secretion in aggregates. In mouse pituitary fragments, LPS-induced ACTH secretion was blocked by My4 and IL-6 antibodies, identically to re-aggregate cell cultures. LPS-induced ACTH secretion, mediated by intrapituitary IL-6, may represent a pituitary-specific mechanism that stimulates the HPA axis during infection/inflammation.
Exp Clin Endocrinol Diabetes 2001
PMID:The intrapituitary stimulatory effect of lipopolysaccharide on ACTH secretion is mediated by paracrine-acting IL-6. 1174 90

We investigated the capacity of human islets to produce monocyte chemoattractant protein-1 (MCP-1). Primary cultures of pancreatic islets expressed and secreted MCP-1, as determined by Northern blot, immunohistochemistry, in situ hybridization, and enzyme-linked immunosorbent assay. The produced MCP-1 was biologically active as it attracted monocytes in chemotaxis assay, and chemotactic activity was almost abrogated by a neutralizing anti-MCP-1 monoclonal antibody. Expression of MCP-1 was increased by primary inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha) and lipopolysaccharide at both the mRNA and protein levels but not by glucose. However, MCP-1 did not modulate insulin secretion. MCP-1 secreted by pancreatic islets plays a relevant role in the clinical outcome of islet transplant in patients with type 1 diabetes. In fact, low MCP-1 secretion resulted as the most relevant factor for long-lasting insulin independence. This finding opens new approaches in the management of human islet transplantation. Finally, the finding that MCP-1 appears constitutively present in normal human islet beta-cells (immunohistochemistry and in situ hybridization), in the absence of an inflammatory infiltrate, suggests that this chemokine could have functions other than monocyte recruitment and opens a new link between the endocrine and immune systems.
Diabetes 2002 Jan
PMID:Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation. 1175 23

Nonenzymatic glycation is increased in diabetes. The role of advanced glycation end products has been implicated in many of the complications of diabetes, whereas the effects of early-glycation Amadori-modified proteins on vascular cells alone are poorly defined. In the present study, we show that glycated serum albumin (GSA) induces a parallel activation of the redox-responsive transcription factors (nuclear factor kappaB) and AP-1 and increases activity of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK in vascular smooth muscle cells (VSMCs). GSA increased expression of early response genes, c-fos and c-jun, and inflammatory genes, monocyte chemoattractant peptide (MCP-1), and interleukin (IL)-6. These effects were comparable to bacterial lipopolysaccharide, tumor necrosis factor-alphaa, (TNF-alphaa), IL-1alphab, angiotensin II, epidermal growth factor, and the phorbol ester PMA. One of signaling pathways by which GSA activates VSMCs appears to be via nuclear factor kappaB activation, leading to induction of MCP-1 and IL-6 gene expression, comparable to the effects of lipopolysaccharide, TNF-alphaa, and IL-1alphab. Another signaling cascade by which GSA activates VSMCs is the ERK-->c-Fos-->AP-1 pathway, which may lead to stimulation of cell proliferation and migration. These effects are comparable to the effects of angiotensin II, epidermal growth factor, and PMA. Incubation of VSMCs with the antioxidant N-acetylcysteine suppressed GSA-elicited mRNA induction of MCP-1 and IL-6. Inhibition of p38 MAPK but not ERK caused attenuation of MCP-1 and IL-6 mRNA induction. Finally, GSA caused a significant stimulation of VSMC growth and migration. These findings suggest that GSA may play a role in diabetic atherogenesis by activating VSMCs, leading to induction of inflammatory mediators in the vessel wall, as well as proliferation and migration of VSMCs.
 ...
PMID:Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). 1179 73

We present here the first report of a metalloporphyrin-based antioxidant that can prevent or delay the onset of autoimmune diabetes. Type 1 diabetes is an autoimmune process whereby T-cells recognize pancreatic beta-cell antigens and initiate a leukocyte infiltrate that produces proinflammatory cytokines and reactive oxygen species (ROS), ultimately leading to beta-cell destruction. Because islet beta-cells have a reduced capacity to scavenge free radicals, they are very sensitive to ROS action. Metalloporphyrin-based superoxide dismutase (SOD) mimics scavenge ROS and protect cells from oxidative stress and apoptosis. To investigate the effect of SOD mimics and the role of oxidative stress in the development of autoimmune diabetes in vivo, we used a diabetogenic T-cell clone, BDC-2.5, to induce rapid onset of diabetes in young nonobese diabetic-severe combined immunodeficient mice (NOD.scid). Disease was significantly delayed or prevented altogether by treatment of recipient mice with an SOD mimic, AEOL-10113, before transfer of the BDC-2.5 clone. To investigate the mechanisms of protection, in vitro assays for T-cell proliferation and gamma-interferon (IFN-gamma) production were carried out using the T-cell clone BDC-2.5. We found that the SOD mimic significantly inhibited antigen-presenting cell-dependent T-cell proliferation and IFN-gamma production in vitro. In addition, pretreatment of lipopolysaccharide (LPS)-stimulated peritoneal macrophages with SOD mimic inhibited the LPS-dependent increase in TNF-alpha as well as the NADPH oxidase-dependent release of superoxide. Finally, this compound protected NIT-1 insulinoma cells from interleukin-1beta and alloxan cytotoxicity in vitro.
Diabetes 2002 Feb
PMID:A metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. 1181 41

Innate immunity includes neutrophil inflammatory function, tissue destruction and regulatory cytokine production. Programmed cell death (apoptosis) is postulated to be a key mechanism for neutrophil elimination during inflammation. The aim of the present study was to evaluate the neutrophil apoptosis in relation to IL-8, IL-10 and IL-12 production in vitro by neutrophils of patients suffering from diabetes mellitus (DM)1 and the first-degree relatives of patients with DM1. The early stage of neutrophils apoptosis was assessed morphologically, and the later stage by DNA-binding dye propidium iodide, both after treatment with lipopolysaccharide (LPS), insulin or anti-CD95 antibody (Ab) as stimulators. CD16 (FcgammaRIII) receptor expression was also evaluated. Production of IL-8, IL-10, and IL-12 cytokine was evaluated in supernatant after neutrophil incubation for 21 h in culture medium alone, in medium in the presence of LPS, insulin or anti-CD95 antibody (Ab). Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) method using commercially available kits. Our study demonstrates that LPS inhibits the early stage of apoptosis (as evaluated morphologically) of healthy donors' neutrophils. The LPS-dependent early apoptosis inhibition of neutrophil of patients with DM1 or in prediabetics was decreased in comparison with control. The later stage of apoptosis of neutrophils treated in vitro with anti-CD95 Ab of patients suffering from DM1 was decreased in comparison with prediabetics and healthy donors (propidium iodide (PI) staining). LPS-induced production of anti-apoptotic cytokines IL-8, IL-10 by neutrophils of prediabetic and patients with DM1 was increased. The formyl-methionyl-leucyl-phenylalanine (fMLP)-induced proapoptotic reactive oxygen intermediates (ROI) production was significantly higher in DM1 patients. We have concluded that neutrophils from prediabetic and diabetic patients demonstrated the misbalance in anti-apoptotic IL-8 and IL-10 cytokine and proapoptotic ROI production. LPS-dependent IL-12 overproduction by neutrophils is responsible for the switch in T helper Th1/Th2 balance to Th1 and in this way may participate in inflammation and autoimmune DM1 progression.
 ...
PMID:The effect of LPS on neutrophils from patients with high risk of type 1 diabetes mellitus in relation to IL-8, IL-10 and IL-12 production and apoptosis in vitro. 1189 38

It has been suggested that the metabolic syndrome and type 2 diabetes are manifestations of the inflammatory host response. This host response is orchestrated by the production of pro- and anti-inflammatory cytokines that are under genetic control. We therefore hypothesized that a low production capacity of interleukin-10 (IL-10), a centrally operating cytokine with strong anti-inflammatory properties, associates with the metabolic syndrome and type 2 diabetes in old age. In the current study, 599 inhabitants of the city of Leiden, age 85 years, were visited at their place of residence. The production capacity of the anti-inflammatory cytokine IL-10 was assessed in a whole-blood assay in which lipopolysaccharide was used as a stimulus. Serum concentrations of lipids, lipoproteins, glucose, and HbA(1c) were determined, and a history of type 2 diabetes was obtained. Serum concentrations of total cholesterol, LDL cholesterol, triglycerides, glucose, and HbA(1c) gradually decreased over strata representing higher IL-10 production capacity, whereas the concentration of HDL cholesterol gradually increased (all P < 0.01). The odds ratio for type 2 diabetes was 2.7 (95% confidence interval 1.5-4.9) when subjects with the lowest IL-10 production capacity were compared with those with the highest IL-10 production capacity. These findings showed that low IL-10 production capacity (i.e., a pro-inflammatory response) is associated with the metabolic syndrome and type 2 diabetes.
Diabetes 2002 Apr
PMID:Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes : the Leiden 85-Plus Study. 1191 30

Human chorionic gonadotrophin (hCG) is a heterodimeric placental glycoprotein hormone required in pregnancy. In human pregnancy urine and in commercial hCG preparations (c-hCG) it occurs in a variety of forms, including breakdown products. Several reports have suggested modulation of the immune system by intact hormone, but such effects of breakdown products have not been reported. In a related article (Hum Immunol 62:1315, 2001), it is reported that a 400-2000 Dalton (Da) fraction from c-hCG and from human pregnancy urine inhibits Th1-mediated diabetes in NOD mice. The active component(s) were called natural (immuno)modulatory pregnancy factor(s) (NMPF). This study reports that a single treatment with the same low molecular weight NMPF fraction up to 24-h after high dose lipopolysaccharide (LPS) injection inhibited septic shock in mice. This counteracting effect of NMPF paralleled the downregulation of the effects of LPS on the production of macrophage migration inhibitory factor (MIF) by spleen cells, on the plasma level of liver aminotransferase, and on the expression of several splenic lymphocyte and macrophage surface markers. Based on the primary structure of the beta-chain of hCG a synthetic hexapeptide Valine-Leucin-Proline-Alanine-Leucine-Proline (VLPALP) was designed, which demonstrated it to have the same protective effects as the 400-2000 Da NMPF fraction. These results indicate a new strategy for the treatment of septic shock and the potential of therapeutic use of this synthetic oligopeptide.
 ...
PMID:Inhibition of septic shock in mice by an oligopeptide from the beta-chain of human chorionic gonadotrophin hormone. 1192 26

Elevated levels of homocyst(e)ine and infection by Chlamydia pneumoniae have been hypothesized individually to play a role in coronary artery disease (CAD), but the mechanisms are unclear. Data on a possible association are not available. We investigated the correlation between IgG antibody titers against C. pneumoniae and fasting plasma homocyst(e)ine in 234 consecutive male patients with CAD. Chlamydial antibodies to a recombinant genus-specific lipopolysaccharide (LPS) were measured with ELISA. Total homocyst(e)ine (tHcy) concentrations were measured by high-performance liquid chromatography (HPLC). Thirty-seven subjects were classified hyperhomocyst(e)inemic (fasting homocyst(e)ine>14 micromol/l, group A), and 197 subjects were below cut-off (tHcy<14 micromol/l, group B). Prevalence of IgG seropositivity against C. pneumoniae was significantly higher in group A (68%) as compared to group B (39%, P=0.002). Antibody titers were also significantly higher in hyperhomocyst(e)inemic subjects than in cases with low homocyst(e)ine levels (P=0.002). Overall titers correlated significantly with tHcy levels (r(2)=0.222, P=0.001). Hyperhomocyst(e)inemia was associated with arterial hypertension (P=0.003), intake of lipid lowering drugs (P=0.022) and quite not with low folate concentration (P=0.052). No association was seen for IgG seropositivity or homocyst(e)ine and age, body mass index, smoking, diabetes, vitamin B(6) and B(12), cholesterol and triglycerides. These data indicate an association between elevated plasma homocyst(e)ine concentrations and chlamydial IgG antibody titers in patients with CAD.
 ...
PMID:Hyperhomocyst(e)inemia and Chlamydia pneumoniae IgG seropositivity in patients with coronary artery disease. 1253 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>