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)

Acute, lethal graft-versus-host disease (GvHD) develops in B6D2F1 hybrid recipients of wild-type, C57BL/6, parental strain grafts; however, when interferon-gamma (IFN-gamma) gene knockout (gko) donors are used, the disease is prolonged and associated with a higher level of engraftment, particularly of T cells. Lesions containing large, mixed cellular infiltrates develop in the skin, liver, pancreas, salivary gland, lung and kidney. In our current study, we wished to determine whether GvHD features a preponderance of T helper 2 (Th2) cytokines in the absence of donor-derived IFN-gamma, and whether autoantibody production, commonly associated with chronic GvHD, also occurs. Because mitogen responsiveness is consistently suppressed in mice with acute GvHD, we wished to measure this response in recipients of IFN-gamma gko grafts. Our findings indicate that spleen cells from the latter produce interleukin (IL)-4, IL-5 and IL-13 in culture, but respond poorly to concanavalin A (Con A) and lipopolysaccharide (LPS). Their sera contain anti-nuclear antibodies (ANA), some of which are specific for double-stranded (ds)DNA and are predominantly immunoglobulin (Ig)M and IgG1. We also noted the presence of numerous eosinophils in the infiltrates developing within the target organs. In some respects, this syndrome bears resemblance to both systemic lupus erythematosus (SLE) and chronic GvHD. However, histological evidence of glomerulonephritis is lacking and proteinuria fails to develop in recipients of IFN-gamma gko grafts, suggesting that IFN-gamma may be necessary for the development of lupus nephritis. On a broader scope, our findings underscore the importance of IFN-gamma in the pathogenetic mechanism of GvHD, and demonstrate that the absence of this cytokine promotes the development of chronic GvHD and autoimmunity.
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PMID:Murine graft-versus-host disease induced using interferon-gamma-deficient grafts features antibodies to double-stranded DNA, T helper 2-type cytokines and hypereosinophilia. 1184 16

The advantages of laparoscopic (LC versus, open cholecystectomy (OC) seems to be related to minimal invasive procedure and to the moderate inflammatory response. The aim of this study is to define the involvement of Th1 (IFN-gamma) and Th2 (IL-4, IL-6, IL-10, IL-13) cytokines production in vivo and in vitro in patients undergoing OC or LC. In 42 patients undergoing LC (n = 22) and OC (n = 20) Th1-like and Th2-like was evaluated before operation and at 6, 24 and 48 hours after operation for white blood cell counting and cytokines (IL-4, IL-6, IL-10, IL-13, IFN-gamma, TNF-alpha) in the sera and in the supernatants from circulating mononuclear cells stimulated with phytohemagglutinin or lipopolysaccharide. The acute phase response cytokine, IL-6, appeared significantly increased following OC than after LC. All other cytokines did not very significantly. In vitro data shows a reduction of IFN-gamma and increase in Th2-like cytokines in OC patients compared with the basal value. In LC subjects we observed an high production of IFN-gamma associated to an increase of Th2-like cytokines, like IL-10 and IL-13, even though IL-4 and IL-6 were unmodified. In contrast to OC, LC did not significantly affect immunocompetence, maintaining a moderate inflammatory response and an adequate balance between Th1 and Th2 cytokine. Furthermore, the strong activation of cells producing Th1-like cytokines in LC patients following mitogen activation indicated a consistent anti-microbial activity, that was not detectable in OC patients, that showed after activation only a Th2 response.
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PMID:Th1-like and Th2-like cytokines in patients undergoing open versus laparascopic cholecystectomy. 1186 4

By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.
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PMID:Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787. 1196 Oct 80

Endothelial cells (EC) play a central role in inflammatory immune responses and efficiently induce effector functions in T cells, despite lacking the classical costimulatory ligands CD80 and CD86. By using the mAb HIL-131 we now demonstrate that human inducible costimulator-ligand (ICOS-L), a molecule related to CD80/CD86, is constitutively expressed on human EC in vivo. In vitro, ICOS-L expression was strongly enhanced on human umbilical vein EC and microvascular EC by the inflammatory cytokines tumor necrosis factor alpha and IL-1beta, and to a lower extent by stimulation of EC by CD40 or lipopolysaccharide. Coculture of MHC class II(+) EC with resting memory CD4(+) T cells in the presence of superantigen led to a marked up-regulation of ICOS on T cells and to the production of Th1 (IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-10, IL-13). When these cocultures were performed in the presence of the inhibitory mAb HIL-131, secretion of all cytokines was reduced by about 50-80%, indicating that ICOS-L is a major costimulator in EC-mediated T cell activation. Taken together, our data suggest an important physiological role of ICOS-L in the reactivation of effector/memory T cells on the endothelium controlling the entry of immune cells into inflamed tissue.
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PMID:ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells. 1198 10

When the brain suffers injury, microglia migrate to the damaged sites and become activated. These activated microglia are not detected several days later and the mechanisms underlying their disappearance are not well characterized. In this study, we demonstrate that interleukin (IL)-13, an anti-inflammatory cytokine, selectively induces cell death of activated microglia in vitro. Cell death was detected 4 days after the coaddition of IL-13 with any one of the microglial activators, lipopolysaccharide (LPS), ganglioside, or thrombin. This cell death occurred in a time-dependent manner. LPS, ganglioside, thrombin, or IL-13 alone did not induce cell death. Among anti-inflammatory cytokines, IL-4 mimicked the effect of IL-13, while TGF-beta did not. Cells treated with IL-13 plus LPS, or IL-13 plus ganglioside, showed the characteristics of apoptosis when analyzed by electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Electron micrographs also showed microglia engulfing neighboring dead cells. We propose that IL-13 and IL-4 induce death of activated microglia, and that this process is important for prevention of chronic inflammation that can cause tissue damage.
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PMID:Interleukin-13 and -4 induce death of activated microglia. 1200 40

Morphological changes observed in OA include cartilage erosion as well as a variable degree of synovial inflammation. Current research attributes these changes to a complex network of biochemical factors, including proteolytic enzymes, that lead to a breakdown of the cartilage macromolecules. Cytokines such as IL-1 and TNF-alpha produced by activated synoviocytes, mononuclear cells or by articular cartilage itself significantly up-regulate metalloproteinases (MMP) gene expression. Cytokines also blunt chondrocyte compensatory synthesis pathways required to restore the integrity of the degraded extrecellular matrix (ECM). Moreover, in OA synovium, a relative deficit in the production of natural antagonists of the IL-1 receptor (IL-1Ra) has been demonstrated, and could possibly be related to an excess production of nitric oxide in OA tissues. This, coupled with an upregulation in the receptor level, has been shown to be an additional enhancer of the catabolic effect of IL-1 in this disease.IL-1 and TNF-alpha significantly up-regulate MMP-3 steady-state mRNA derived from human synovium and chondrocytes. The neutralization of IL-1 and/or TNF-alpha up-regulation of MMP gene expression appears to be a logical development in the potential medical therapy of OA. Indeed, recombinant IL-1receptor antagonists (ILRa) and soluble IL-1 receptor proteins have been tested in both animal models of OA for modification of OA progression. Soluble IL-1Ra suppressed MMP-3 transcription in the rabbit synovial cell line HIG-82. Experimental evidence showing that neutralizing TNF-alpha suppressed cartilage degradation in arthritis also support such strategy. The important role of TNF-alpha in OA may emerge from the fact that human articular chondrocytes from OA cartilage expressed a significantly higher number of the p55 TNF-alpha receptor which could make OA cartilage particularly susceptible to TNF-alpha degradative stimuli. In addition, OA cartilage produces more TNF-alpha and TNF anglealpha convertase enzyme (TACE) mRNA than normal cartilage. By analogy, an inhibitor to the p55 TNF-alpha receptor may also provide a mechanism for abolishing TNF-alpha-induced degradation of cartilage ECM by MMPs. Since TACE is the regulator of TNF-alpha activity, limiting the activity of TACE might also prove efficacious in OA. IL-1 and TNF-alpha inhibition of chondrocyte compensatory biosynthesis pathways which further compromise cartilage repair must also be dealt with, perhaps by employing stimulatory agents such as transforming growth factor-beta or insulin-like growth factor-I. Certain cytokines have antiinflammatory properties. Three such cytokines - IL-4, IL-10, and IL-13 - have been identified as able to modulate various inflammatory processes. Their antiinflammatory potential, however, appears to depend greatly on the target cell. Interleukin-4 (IL-4) has been tested in vitro in OA tissue and has been shown to suppress the synthesis of both TNF-alpha and IL-1beta in the same manner as low-dose dexamethasone. Naturally occurring antiinflammatory cytokines such as IL-10 inhibit the synthesis of IL-1 and TNF-alpha and can be potential targets for therapy in OA. Augmenting inhibitor production in situ by gene therapy or supplementing it by injecting the recombinant protein is an attractive therapeutic target, although an in vivo assay in OA is not available, and its applicability has yet to be proven. Similarly, IL-13 significantly inhibits lipopolysaccharide (LPS)-induced TNF-alpha production by mononuclear cells from peripheral blood, but not in cells from inflamed synovial fluid. IL-13 has important biological activities: inhibition of the production of a wide range of proinflammatory cytokines in monocytes/macrophages, B cells, natural killer cells and endothelial cells, while increasing IL-1Ra production. In OA synovial membranes treated with LPS, IL-13 inhibited the synthesis of IL-1beta, TNF-alpha and stromelysin, while increasing IL-1Ra production.In summary, modulation of cytokines that control MMP gene up-regulation would appear to be fertile targets for drug development in the treatment of OA. Several studies illustrate the potential importance of modulating IL-1 activity as a means to reduce the progression of the structural changes in OA. In the experimental dog and rabbit models of OA, we have demonstrated that in vivo intraarticular injections of the IL-Ra gene can prevent the progression of structural changes in OA. Future directions in the research and treatment of osteoarthritis (OA) will be based on the emerging picture of pathophysiological events that modulate the initiation and progression of OA.
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PMID:The role of cytokines in osteoarthritis pathophysiology. 1208 86

The active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is a potent immunomodulator known to affect T-cells through targeting antigen-presenting cells such as dendritic cells (DCs). We studied the effects of a novel nonhypercalcemic 1,25(OH)(2)D(3) analog, TX527, on DC differentiation, maturation, and function with respect to stimulation of a committed human GAD65-specific autoreactive T-cell clone. Continuous addition of TX527 impaired interleukin (IL)-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF)-driven DC differentiation as well as lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma)-induced maturation into Th1-promoting DC (DC1), as characterized by marked changes in DC morphology and abrogation of IL-12p70 release upon CD40 ligation. Addition of TX527 during maturation did not affect DC morphology but significantly changed DC cytokine profiles. The potential of treated DCs to alter the response pattern of committed autoreactive T-cells was found to depend on the timing of TX527 exposure. Continuously TX527-treated DCs significantly inhibited T-cell proliferation and blocked IFN-gamma, IL-10, but not IL-13 production, whereas DCs treated during maturation failed to inhibit T-cell proliferation but affected IL-10 and IFN-gamma production. Collectively, we provide evidence that nonhypercalcemic TX527 is a potent in vitro DC modulator, yielding DCs with the potential to change cytokine responses of committed autoreactive T-cells.
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PMID:Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). 1208 41

To address the complex chronic effector properties of interleukin (IL)-10, we generated transgenic mice in which IL-10 was overexpressed in the lung. In these mice, IL-10 inhibited endotoxin-induced tumor necrosis factor production and neutrophil accumulation. IL-10 also caused mucus metaplasia, B and T cell-rich inflammation, and subepithelial fibrosis and augmented the levels of mRNA encoding Gob-5, mucins, and IL-13. In mice bred to have null mutations of IL-13, IL-4R(alpha), or STAT-6, transgenic IL-10 did not induce mucus metaplasia but did induce inflammation and fibrosis. IL-10 was also a critical mucin regulator of virus-induced mucus metaplasia. Thus, IL-10, although inhibiting lipopolysaccharide-induced inflammation, also causes mucus metaplasia, tissue inflammation, and airway fibrosis. These responses are mediated by multiple mechanisms with mucus metaplasia being dependent on and the inflammation and fibrosis being independent of an IL-13/IL-4R(alpha)/STAT-6 activation pathway.
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PMID:Transgenic overexpression of interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and -independent pathways. 1210 90

Enriched populations of human microglial cells were isolated from mixed cell cultures prepared from embryonic human telencephalon tissues. Human microglial cells exhibited cell type-specific antigens for macrophage-microglia lineage cells including CD11b (Mac-1), CD68, B7-2 (CD86), HLA-ABC, HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1), and actively phagocytosed latex beads. Gene expression and protein production of cytokines, chemokines and cytokine/chemokine receptors were investigated in the purified populations of human microglia. Normal unstimulated human microglia expressed constitutively mRNA transcripts for interleukin- 1beta (IL-1beta) -6, -8, -10, -12, -15, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1), while treatment with lipopolysaccharide (LPS) or amyloid beta peptides (Abeta) led to increased expression of mRNA levels of IL-8, IL-10, IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human microglia, in addition, expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R, IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, and IL-15R. Enzyme-linked immunosorbent assays (ELISA) showed increased protein levels in culture media of IL-1beta, IL-8, TNF-alpha, and MIP-1alpha in human microglia following treatment with LPS or Abeta. Increased TNF-alpha release from human microglia following LPS treatment was completely inhibited with IL-10 pretreatment, but not with IL-6, IL-9, IL-12, IL-13, or transforming growth factor-beta (TGF-beta). Present results should help in understanding the basic microglial biology, but also the pathophysiology of activated microglia in neurological diseases such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, stroke, and neurotrauma.
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PMID:Cytokines, chemokines, and cytokine receptors in human microglia. 1211 20

The common gamma (gamma c) chain, shared by Th1 and Th2 cytokines, is fundamental for the activation of hematopoietic cells, but its role in non-hematopoietic tissues has not been explored. Here we show that in normal lung fibroblasts IL-4 and IL-13 induce the expression of the gamma c chain and its association with Janus kinase (JAK) 3, while lung myofibroblasts constitutively express a gamma c chain displaying a limited association with JAK3. In the latter cells, without exogenous cytokines, gamma c/JAK3 controls, through autocrine loops, tyrosine kinase (TYK) 2 phosphorylation and the balance between functional (IL-4Ralpha, IL-13Ralpha 1) and decoy (IL-13Ralpha 2) high-affinity receptors. Moreover, JAK3 is also associated with a pre-phosphorylated IL-4Ralpha and CD40. This novel "heterotrimer" (p-IL-4Ralpha, CD40/JAK3) is functional and controls STAT3 phosphorylation and CD40 expression, as shown by use of the specific JAK3 inhibitor WHI-P31. In basal culture conditions, CD40 signaling could be induced by the transient establishment of inter-fibroblastic CD40/CD40 ligand (CD40L) functional bridges. Indeed, powerful pro-inflammatory stimuli such as lipopolysaccharide and thrombin can rapidly mobilize CD40L at the surface of lung myofibroblasts. These interactions are modified by IL-13, which triggers the formation of a new type of functional receptor (p-IL-4Ralpha /IL-13Ralpha 1/gamma c) and also the recruitment and the phosphorylation of JAK3. Treatment with JAK3 inhibitors blocks IL-13-induced phosphorylation of JAK2, TYK2 and STAT3, but not of JAK1 and STAT6. These data underline (1) the pivotal role of the gamma c chain, CD40/CD40L, JAK3 and IL-13 in the inflammatory-like activation of lung myofibroblasts, (2) the cell-type restraint effects of IL-13 on these cells, and (3) the potential usefulness of JAK3 inhibitors in the treatment of asthma.
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PMID:Human lung myofibroblasts as effectors of the inflammatory process: the common receptor gamma chain is induced by Th2 cytokines, and CD40 ligand is induced by lipopolysaccharide, thrombin and TNF-alpha. 1220 28


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