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 Fas/APO-1 cytotoxic pathway plays an important role in the regulation of peripheral immunity. Recent evidence indicates that this regulatory function operates through deletion of activated T and B lymphocytes by CD4+ T cells expressing the Fas ligand. Because macrophages play a key role in peripheral immunity, we asked whether Fas was involved in T-cell-macrophage interactions. Two-color flow cytometry revealed that Fas receptor (FasR) was expressed on resting murine peritoneal macrophages. FasR expression was upregulated after activation of macrophages with cytokines or lipopolysaccharide, although only tumor necrosis factor-alpha rendered macrophages sensitive to anti-FasR antibody-mediated death. To determine the consequence of antigen presentation by macrophages to CD4+ T cells, macrophages were pulsed with antigen and then incubated with either Th1 or Th2 cell lines or clones. Th1, but not Th2, T cells induced lysis of 60-80% of normal macrophages, whereas macrophages obtained from mice with mutations in the FasR were totally resistant to Th1-mediated cytotoxicity. Macrophage cytotoxicity depended upon specific antigen recognition by T cells and was major histocompatibility complex restricted. These findings indicate that, in addition to deletion of activated lymphocytes, Fas plays an important role in deletion of activated macrophages after antigen presentation to Th1 CD4+ T cells. Failure to delete macrophages that constitutively present self-antigens may contribute to the expression of autoimmunity in mice deficient in FasR (lpr) or Fas ligand (gld).
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PMID:Th1 CD4+ lymphocytes delete activated macrophages through the Fas/APO-1 antigen pathway. 747 70

Fas ligand (FasL, Apo-1L) is a member of the tumor necrosis factor protein family and binding to its receptor (Fas, Apo-1, CD95) triggers cell death through apoptosis. Ligand expression is restricted to cells with known cytolytic activity and found on hematopoietic cells of the T cell and natural killer lineage. Here we provide evidence that B lymphocytes can express FasL. Flow cytometric analysis revealed that FasL is expressed on the surface of B cells upon stimulation with either lipopolysaccharide or phorbol 12-myristate 13-acetate/ionomycin. FasL expression on activated B cells was confirmed by western blot and reverse transcriptase polymerase chain reaction analysis. FasL on B cells is functional since lipopolysaccharide-activated B lymphocytes derived from wild type, but not from gld mutant mice, were able to kill Fas-sensitive target cells. Our data suggest that the Fas system may contribute to the control of B cell homeostasis.
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PMID:Activated B cells express functional Fas ligand. 860 44

We have utilized synthetic ribozymes to modulate the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-alpha) by peritoneal cells. Two hammerhead ribozymes (mRz1 and mRz2) were prepared by transcription in vitro and their activities in vitro and in vivo were investigated. Both ribozymes cleaved their RNA target with an apparent turnover number (kcat) of 2 min(-1), and inhibited TNF-alpha gene expression in vitro by 50% and 70%, respectively. When mRz1 and mRz2, entrapped in liposomes, were delivered into mice by intraperitoneal injection, they inhibited LPS-induced TNF-alpha gene expression in vivo with mRz2 being the most effective. This enhanced activity could result from the facilitation of catalysis by cellular endogenous proteins, since they specifically bind to mRz2 as compared to mRz1. Furthermore, a significant mRz2 activity can be recovered from peritoneal cells 2 days post-administration in vivo. The anti-TNF-alpha ribozyme treatment in vivo resulted in a more significant reduction of LPS-induced IFN-gamma protein secretion compared to IL-10. In contrast to this pleiotropic effect, the anti-TNF-alpha ribozyme treatment did not affect the heterogenous expression of Fas ligand by peritoneal cells, indicating the specificity of the treatment. Taken together, the present data indicate that the biological effects of TNF-alpha can be modulated by ribozymes. In addition, the data suggest that ribozymes can be administered in a drug-like manner, and therefore indicate their potential in clinical applications.
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PMID:Ribozyme modulation of lipopolysaccharide-induced tumor necrosis factor-alpha production by peritoneal cells in vitro and in vivo. 864 63

Fas is a cell-surface protein of 45 kDa. Binding of the Fas ligand (FasL) to Fas induces apoptosis in Fas-bearing cells. Analysis of mouse mutants in either Fas or FasL have indicated that the Fas system is involved in apoptosis of lymphocytes. To identify the cells expressing Fas, mouse spleen sections were analyzed by in situ hybridization and immunohistochemistry. Fas mRNA was detected in the T cells of the inner region of the periarterial lymphatic sheath and the inner lumen of the marginal zone. The cells in the outer region of the periarterial lymphatic sheath weakly expressed Fas mRNA, whereas it was abundant in the B cells of germinal centers. Immunizing mice with keyhole limpet hemocyanin induced formation of many germinal centers in the spleen. The B cells in the activated germinal center expressed abundant Fas and underwent apoptosis. The in vitro activation of splenocytes with lipopolysaccharide induced Fas expression in B cells and the B cells became sensitive to the Fas-mediated apoptosis. These results suggest that Fas is involved in the activation-induced death of B cells.
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PMID:Expression of Fas in B cells of the mouse germinal center and Fas-dependent killing of activated B cells. 874 64

Autoimmune-prone MRL/lpr mice, homozygous for the lpr mutation, exhibit defective apoptosis and develop generalized lymphoproliferation with the accumulation of a double-negative (DN: CD4- CD8-) T cell population. The capacity of lpr T lymphocytes to effectuate Fas- and perforin-mediated cytotoxicity was investigated. Spleen and lymph nodes cells spontaneously lyse Fas- targets (thymocytes) through a Fas-mediated mechanism as a consequence of their overexpression of Fas ligand (FasL) confirmed by semiquantitative reverse transcription (RT)-PCR and immunoprecipitation analysis. This cytotoxicity was greatly increased after stimulation of the effectors by phorbol myristate acetate (PMA) + ionomycin. Under these conditions, MRL/lpr spleen and LN cells exhibited strong Fas-mediated Ca2+-independent cytotoxic activity against wild-type Fas+ (H-2 compatible or incompatible) thymocytes or lipopolysaccharide (LPS)-transformed blast cells. Such Fas-mediated cytotoxic activity was also observed with C57BL/6-lpr, but never with wild-type C57BL/6 or MLR+/+ effectors. Depletion experiments showed that the effector cells of this Fas-mediated cytotoxicity were DN T cells. This subset, which represent in vivo activated T cells, can spontaneously lyse Fas+ targets by a mechanism that does not need the interaction of the T cell receptor (TCR) with major histocompatibility complex molecule plus antigen. This lytic potential is increased by PMA + ionomycin, which sends a second activation signal to these primed T cells. Therefore, the small amounts of Fas receptor expressed on MRL/lpr tissues may account for their nonspecific autoimmune attack by DN cells. In Con A-containing medium, which allows detection of the perforin-mediated pathway against Fas targets, cytotoxic CD8+ effectors were detected that are able to kill lpr thymocytes via a Ca2+-dependent pathway. Thus, in MRL/lpr mice, these CD8+ cells could constitute potent cytotoxic effectors against cells presenting antigen to their TCR.
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PMID:MRL/lpr CD4- CD8- and CD8+ T cells, respectively, mediate Fas-dependent and perforin cytotoxic pathways. 904 12

The Fas ligand (FasL) is expressed in activated T cells and induces apoptosis in Fas-bearing cells. A cytotoxic T lymphocyte (CTL) clone specific for hepatitis B surface antigen (HBsAg) causes an acute liver disease in HBsAg transgenic mice. Here we observed that the CTL clone killed hepatocytes expressing HBsAg in a Fas-dependent manner. Administration of the soluble form of Fas into HBsAg transgenic mice prevented the CTL-induced liver disease. In the second model, mice were primed with Propionibacterium acnes. A subsequent challenge with lipopolysaccharide (LPS) killed the mice by inducing liver injury. Neutralization of FasL rescued the mice from LPS-induced mortality, and Fas-null mice were resistant to LPS-induced mortality. These results suggest that FasL has an essential role in the development of hepatitis.
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PMID:Essential roles of the Fas ligand in the development of hepatitis. 909 70

Accumulating evidence implicates tumor necrosis factor (TNF) and Fas systems in liver injury, although the interaction between these two systems remains to be investigated. In this study, we examined Propionibacterium acnes-primed TNF receptor p55-deficient (TNFRp55-/-) or Fas-deficient MRL/MpJ Lpr/Lpr mice challenged with lipopolysaccharide (LPS). Priming with P. acnes caused mononuclear cell infiltration into the hepatic lobules and granuloma formation in the livers of TNFRp55 wild-type mice. Subsequent LPS challenge caused massive liver injury and a marked increase in transaminase levels, leading to acute lethality in control wild-type mice. In contrast, the same treatment caused few pathological changes in livers of TNFRp55-/- mice, and all animals survived. P. acnes and subsequent LPS challenge induced granuloma formation and apoptotic changes, respectively, in livers of MRL/MpJ Lpr/Lpr mice. However, liver injury was 50% of that in control MRL/MpJ +/+ mice, suggesting some role of the Fas-Fas ligand system in this liver injury model. On the other hand, an agonistic anti-Fas antibody caused massive apoptosis and hemorrhagic changes of the liver without any priming with P. acnes, leading to death in both TNFRp55-/- and control wild-type mice. These results suggest that TNFRp55 but not Fas was involved in P. acnes-induced granuloma formation as well as subsequent LPS-induced liver injury and that TNFRp55 and Fas independently induced apoptosis of hepatocytes in vivo.
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PMID:Tumor necrosis factor receptor p55 is essential for intrahepatic granuloma formation and hepatocellular apoptosis in a murine model of bacterium-induced fulminant hepatitis. 912 77

Activation of T cells was shown to up-regulate the Fas ligand (FasL) which binds to the CD95 (APO-1/Fas) antigen and mediates activation-induced cell death (AICD) of activated T cells and T lymphoma cells. A recent report showed that mouse B cells express the FasL upon activation with lipopolysaccharide (LPS). We therefore asked whether activation of human B cells induces expression of FasL and whether AICD is mediated, as in T cells, through autocrine production of the FasL. We used human tonsillar B cells and Burkitt lymphoma cell lines which were activated by CD40 ligand, surface (s)IgM cross-linking, or LPS. Northern and Western blot analysis failed to detect FasL during B cell activation or AICD of both normal and malignant B cells. Low-level expression of FasL was detected by reverse transcriptase-polymerase chain reaction. Functional experiments, however, showed that FasL is not functionally expressed upon activation. IgM-mediated AICD in the tonsillar or Burkitt lymphoma B cells could not be inhibited by FasL blocking. Thus, our data show that, in contrast to T cells, activation of normal or malignant human B cells does not lead to functional FasL expression.
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PMID:Activation and activation-induced death of human tonsillar B cells and Burkitt lymphoma cells: lack of CD95 (Fas/APO-1) ligand expression and function. 913 Jun 60

On the basis of the strict analogies between polymorphonuclear cell (PMN) alterations in the aging and depressed functional capacities displayed by apoptotic PMN, we investigated the possible occurrence of age-associated changes in neutrophil apoptosis, either spontaneous or induced by Fas antigen (CD95) activation. In both cases, old subjects exhibited a time course kinetics of neutrophil apoptosis, as assessed by morphologic and quantitative DNA fragmentation analysis, which overlapped that observed in the young. These findings were confirmed by DNA ladder analysis, showing a progressive increase in DNA cleavage products in cells cultured in medium alone or added with agonistic anti-Fas IgM (CH-11) monoclonal antibodies (mAbs), after 12 and 6 hr of incubation, respectively. Aged purified neutrophils constitutively expressed CD95, at levels similar to those observed in the young. Moreover, although we failed to detect Fas ligand expression on PMN surface, treatment of cell cultures with antagonistic anti-Fas IgG1 (ZB4) mAbs determined a significant inhibition of spontaneous apoptosis in neutrophils from both groups of subjects, thus suggesting that the Fas/Fas ligand system is in fact involved in such an event. The results indicate that the overall intrinsic mechanisms regulating neutrophil cell death are not affected by age. Yet aged neutrophils showed a diminished capacity to be rescued by proinflammatory mediators, such as granulocyte-monocyte colony-stimulating factor, granulocyte colony-stimulating factor, and bacterial lipopolysaccharide, following Fas activation. This may hamper the accumulation of functionally active cells in inflammatory areas in vivo, thus contributing to the increased susceptibility of elderly individuals to life-threatening infections.
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PMID:Spontaneous and Fas-induced apoptotic cell death in aged neutrophils. 979 24

Thymus and activation-regulated chemokine (TARC) is a recently identified lymphocyte-directed CC chemokine which specifically chemoattracts T helper type 2 CD4(+) T cells in human. To establish the pathophysiological roles of TARC in vivo, we investigated whether a monoclonal antibody (mAb) against TARC could inhibit the induction of hepatic lesions in murine model using Propionibacterium acnes and lipopolysaccharide (LPS). P. acnes-induced intrahepatic granuloma formation in the priming phase is essential to the subsequent liver injury elicited by a low dose of LPS. The priming phase appears to be dominated by Th1 type immune responses determined by the profile of chemokine and chemokine receptor expression. TARC was selectively produced by granuloma-forming cells, and CC chemokine receptor 4 (CCR4)-expressing CD4(+) T cells migrated into the liver after LPS administration. In vivo injection of anti-TARC mAb just before LPS administration protected the mice from acute lethal liver damage, which was accompanied by a significant reduction of both CCR4 mRNA expression and IL-4 production by liver-infiltrating CD4(+) T cells. Moreover, both TNF-alpha and Fas ligand expressions in the liver were decreased by anti-TARC treatment. These results suggest that recruitment of IL-4-producing CCR4(+) CD4(+) T cells by granuloma-derived TARC into the liver parenchyma may be a key cause of massive liver injury after systemic LPS administration.
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PMID:Pivotal role of TARC, a CC chemokine, in bacteria-induced fulminant hepatic failure in mice. 983 18


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