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)

The free radical trapping compound phenyl N-tert-butylnitrone (PBN) provides potent protection against lethal endotoxemia in rodents, but the mechanism of this protection is not well understood. The objective of this study was to show that PBN administration in lipopolysaccharide- (LPS) induced endotoxemia promotes enhanced production of endogenous interleukin 10 (IL-10), and the expressed IL-10 is a causal factor in the protection from endotoxemia. We show the amplified expression of IL-10 in liver and plasma in PBN- (150 mg/kg) plus LPS- (4 mg/kg) treated rats using ribonuclease protection assay (RPA) and ELISA. In situ hybridization was utilized to visualize the overexpression of the IL-10 gene, and ELISA was used to determine plasma IL-10 and TNFalpha levels. Plasma IL-10 showed a 3-fold increase in PBN/LPS- treated rats compared to those treated with LPS alone, and in contrast, TNFalpha level decreased by more than 90%. However, the administration of PBN alone induced no IL-10 production. Immunoneutralization of IL-10 through anti-IL-10 antibody administration to PBN/LPS-treated rats abrogated PBN's suppression of systemic nitric oxide (NO) formation, a surrogate marker for the severity of endotoxemia, indicating that IL-10 is a causal factor for the protection. In these experiments, systemic NO level was quantified using an in vivo electron paramagnetic resonance (EPR) NO-trapping technique. Gel-shift and immunohistochemical analyses indicated that the transcription factor NF-kappaB was deactivated after PBN treatment, suggesting that NF-kappaB deactivation is closely involved in IL-10 overexpression.
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PMID:Interleukin-10 overexpression mediates phenyl-N-tert-butyl nitrone protection from endotoxemia. 1190 Mar 40

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the world's most common known human genetic polymorphisms, but the pathophysiology of the defect remains largely unknown. In the present study, we compared hematology parameters and ex vivo monocyte cytokine responses in non-deficient and G6PD-deficient trauma patients. Deficient and non-deficient, moderately injured, trauma patients exhibited similar hematology profiles at the time of hospital admission. In contrast to non-deficient patients, G6PD-deficient patients were anemic 2 days post-injury. Monocytes from deficient individuals produced 50% less interleukin 10 (IL-10) in response to LPS and >90% less IL-10 in response to PMA, compared with non-deficient patients, 2 days post-injury. The presence of phenylhydrazine-treated, opsonized, autologous RBC (OX-RBC), alone had no effect on IL-10 production by non-deficient or deficient monocytes, whereas IL-10 responses to lipopolysaccharide (LPS) were augmented by OX-RBC in both groups. However, IL-10 production was markedly lower by monocytes from G6PD-deficient than non-deficient patients after stimulation with LPS plus OX-RBC. TNF-alpha production following PMA was similar in deficient and non-deficient patients, and the differences following LPS or LPS plus OX-RBC stimulation were moderate between deficient and non-deficient samples. Interferon (IFN)-gamma production ex vivo was doubled by OX-RBC treatment alone, but it was not stimulated by LPS treatment. IFN-gamma production was similar in non-deficient and G6PD-deficient patients. These data suggest that the observed differences in IL-10 responses between G6PD-deficient and non-deficient patients are not attributable to differences in TNF-alpha or IFN-gamma production. Taken together, our data suggest that a reduction in the capacity to produce IL-10 may be an intrinsic characteristic of G6PD-deficient monocytes. An attenuated IL-10 production may be a contributing mechanism in the previously observed augmented inflammatory response in severely injured G6PD-deficient compared with non-deficient trauma patients.
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PMID:Attenuated monocyte IL-10 production in glucose-6-phosphate dehydrogenase-deficient trauma patients. 1209 28

Progressing tumors in man and mouse are often infiltrated by dendritic cells (DCs). Deficient antitumor immunity could be related to a lack of tumor-associated antigen (TAA) presentation by tumor-infiltrating DCs (TIDCs) or to a functional defect of TIDCs. Here we investigated the phenotype and function of TIDCs in transplantable and transgenic mouse tumor models. Although TIDCs could encompass various known DC subsets, most had an immature phenotype. We observed that TIDCs were able to present TAA in the context of major histocompatibility complex class I but that they were refractory to stimulation with the combination of lipopolysaccharide, interferon gamma, and anti-CD40 antibody. We could revert TIDC paralysis, however, by in vitro or in vivo stimulation with the combination of a CpG immunostimulatory sequence and an anti-interleukin 10 receptor (IL-10R) antibody. CpG or anti-IL-10R alone were inactive in TIDCs, whereas CpG triggered activation in normal DCs. In particular, CpG plus anti-IL-10R enhanced the TAA-specific immune response and triggered de novo IL-12 production. Subsequently, CpG plus anti-IL-10R treatment showed robust antitumor therapeutic activity exceeding by far that of CpG alone, and elicited antitumor immune memory.
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PMID:Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. 1218 45

Mice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo. Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h post-shock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-alpha (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-alpha and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis.
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PMID:Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice. 1229 49

Glucocorticoids and interleukin 10 (IL-10) prevent macrophage activation. In murine lymphocytes, glucocorticoids induce expression of glucocorticoid-induced leucine zipper (GILZ), which prevents the nuclear factor kappaB (NF-kappaB)-mediated activation of transcription. We investigated whether GILZ could account for the deactivation of macrophages by glucocorticoids and IL-10. We found that GILZ was constitutively produced by macrophages in nonlymphoid tissues of humans and mice. Glucocorticoids and IL-10 stimulated the production of GILZ by macrophages both in vitro and in vivo. Transfection of the macrophagelike cell line THP-1 with the GILZ gene inhibited the expression of CD80 and CD86 and the production of the proinflammatory chemokines regulated on activation normal T-cell expressed and secreted (CCL5) and macrophage inflammatory protein 1alpha (CCL3). It also prevented toll-like receptor 2 production induced by lipopolysaccharide, interferongamma, or an anti-CD40 mAb, as well as NF-kappaB function. In THP-1 cells treated with glucocorticoids or IL-10, GILZ was associated with the p65 subunit of NF-kappaB. Activated macrophages in the granulomas of patients with Crohn disease or tuberculosis do not produce GILZ. In contrast, GILZ production persists in tumor-infiltrating macrophages in Burkitt lymphomas. Therefore, GILZ appears to play a key role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL-10. Glucocorticoid treatment stimulates GILZ production, reproducing an effect of IL-10, a natural anti-inflammatory agent. The development of delayed-type hypersensitivity reactions is associated with the down-regulation of GILZ gene expression within lesions. In contrast, the persistence of GILZ gene expression in macrophages infiltrating Burkitt lymphomas may contribute to the failure of the immune system to reject the tumor.
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PMID:Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10. 1239 3

Secreted proteins of Mycobacterium tuberculosis are major targets of the specific immunity in tuberculosis and constitute promising candidates for the development of more efficient vaccines and diagnostic tests. We show here that M. tuberculosis-specific antigen 10 (MTSA-10, originally designated CFP-10) can bind to the surface of mouse J774 macrophage-like cells and stimulate the secretion of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). MTSA-10 also synergized with gamma interferon (IFN-gamma) for the induction of the microbicidal free radical nitric oxide (NO) in J774 cells, as well as in bone marrow-derived and peritoneal macrophages. On the other hand, pretreatment of J774 cells with MTSA-10 markedly reduced NO but not TNF-alpha or interleukin 10 (IL-10) release upon subsequent stimulation with lipopolysaccharide or the cell lysate of M. tuberculosis. The presence of IFN-gamma during stimulation with M. tuberculosis lysate antagonized the desensitizing effect of MTSA-10 pretreatment on macrophage NO production. The activation of protein tyrosine kinases (PTK) and the serine/threonine kinases p38 MAPK and ERK was apparently required for MTSA-10 induction of TNF-alpha and NO release, as revealed by specific kinase inhibitors. However, only p38 MAPK activity, not PTK or ERK activity, was partly responsible for MTSA-10-mediated macrophage desensitization. The modulation of macrophage function by MTSA-10 suggests a novel mechanism for its involvement in immunopathogenesis of tuberculosis and might have implications for the prevention, diagnosis, and therapy of this disease.
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PMID:Effect of Mycobacterium tuberculosis-specific 10-kilodalton antigen on macrophage release of tumor necrosis factor alpha and nitric oxide. 1243 25

Monophosphoryl lipid A (MPL) is a nontoxic derivative of lipopolysaccharide (LPS) that exhibits adjuvant properties similar to those of the parent LPS molecule. However, the mechanism by which MPL initiates its immunostimulatory properties remains unclear. Due to the involvement of Toll-like receptors in recognizing and transducing intracellular signals in response to LPS, the aim of the present study was to determine the ability of MPL to utilize the Toll-like receptor 2 (TLR2) and TLR4. We provide evidence that MPL differentially utilizes TLR2 and TLR4 for the induction of tumor necrosis factor alpha, interleukin 10 (IL-10), and IL-12 by purified human monocytes as well as by human peripheral blood mononuclear cells. Assessment of NF-kappa B activity demonstrated that MPL utilized TLR2 and especially TLR4 for the activation of NF-kappa B p65 by human monocytes. In addition, stimulation of human monocytes by MPL led to an up-regulation of the costimulatory molecules CD80 and CD86, an effect that could be reduced by pretreatment of cells with a monoclonal antibody to TLR2 or TLR4. Analysis of MPL-induced activation of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases revealed that MPL utilized both TLR2 and TLR4 for the phosphorylation of ERK1/2, while TLR4 was the predominant receptor involved in the ability of MPL to phosphorylate p38. Moreover, using selective inhibitors for MAP kinase kinase (PD98059) and p38 (SB203580), we show that ERK1/2 exhibited differential effects on production of TNF-alpha and IL-12 p40 by human monocytes, whereas MPL-induced activation of p38 appeared to be predominantly involved in production of IL-10 and IL-12 p40 by MPL-stimulated monocytes. Taken together, these findings aid in understanding the cellular mechanisms by which MPL induces host cell activation and subsequent adjuvant properties.
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PMID:Role of innate immune factors in the adjuvant activity of monophosphoryl lipid A. 1270 21

Immune cell trafficking and activity are implicated in the parturition process, but little is known about the role of macrophages in control of uterine contractility at term. In the present study, we tested the hypothesis that endotoxin (lipopolysaccharide [LPS]) enhances uterine contractile activity through a mechanism that involves activation of resident macrophages. Various uterotonins and anti-inflammatory mediators were added to a standard muscle bath preparation that contained strips of uterus from Day 15 pregnant C3H/HeN mice. Spontaneous and agonist-induced contractile activity was enhanced following LPS treatment. LPS increased amplitude but not frequency of contractions. Addition of anti-inflammatory cytokines, interleukin 10 or transforming growth factor beta, to suppress macrophage activation did not block LPS-induced increases in contractility. By contrast, indomethacin given to block prostaglandin production suppressed the LPS-induced increase in amplitude of contractions. These findings suggest that an inflammatory response, possibly mediated by activation of macrophages and prostaglandins, participates in the regulation of amplitude but not frequency of contractile activity by the murine uterus before onset of parturition.
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PMID:Effects of endotoxin and macrophage-related cytokines on the contractile activity of the gravid murine uterus. 1277 33

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II-restricted interferon gamma-producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.
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PMID:CD4+ CD25+ regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo. 1287 59

The balance between proinflammatory and anti-inflammatory processes is of key importance in the reaction of the body to infection, injury, and surgical trauma. Drugs commonly used in anesthesia and intensive care may modulate immunological reactions by influencing intercellular communication through modification of cytokine response and fluctuation of peripheral immune cells such as natural killer (NK) cells, B cells, and T lymphocyte subpopulations (CD4+ and CD8+ cells). To examine the effects of general anesthesia with the hypnotic agent propofol and the opioid fentanyl, 30 patients undergoing minor elective orthopedic surgery were studied before and 20 min after application of the anesthetic drugs, but before the start of surgery. We found a significant enhancement of TNF-alpha and IL-1beta release in lipopolysaccharide (LPS)-stimulated whole blood cultures after induction of anesthesia. Similar results were observed with interferon-gamma (IFN-gamma) in cultures stimulated with phytohemagglutinin (PHA). Conversely, synthesis of the anti-inflammatory cytokine interleukin 10 (IL-10) decreased significantly in LPS-stimulated cultures. During general anesthesia, we found a decrease of circulating lymphocytes, characterized by a significant increase in the percentage of T lymphocytes in favor of CD4+ cells, increased B lymphocytes, and a significant decrease of NK cells. These data suggest that anesthesia with propofol and fentanyl promotes proinflammatory immune responses and influences peripheral lymphocyte composition in patients, which may subsequently affect pathophysiological processes during opioid-based anesthesia.
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PMID:Early alterations in the number of circulating lymphocyte subpopulations and enhanced proinflammatory immune response during opioid-based general anesthesia. 1292 91


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