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)

Tumour necrosis factor (TNF) plays a pivotal role in the induction of cerebral complications during Plasmodium falciparum malaria. TNF secretion by macrophages can be induced by lipopolysaccharide (LPS) and by P. falciparum antigens, but it is unclear whether similar mechanisms control the monokine expression in both cases. The signal transduction pathway by which parasite antigens induce TNF secretion remains to be established. The results reported here, using various inhibitors of second messenger pathways, clearly demonstrate that the signal transduction leading to TNF secretion is mediated partly through protein kinase C and calmodulin-dependent protein kinase activation. Furthermore, this signal seems to be differentially regulated after LPS or parasite stimulation, since cyclo-oxygenase inhibition by indomethacin resulted in twofold more TNF production enhancement with LPS stimulation than with parasite stimulation. The nature of the receptor involved in the parasite induced-macrophage stimulation remains obscure. However, the results discussed here indicate that parasite antigens stimulate multiple signal transduction pathways via G protein. Identification of the different pathways involved in these receptor-mediated events may be invaluable in the development of specific inhibitors against TNF over-production during cerebral malaria.
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PMID:Signal transduction pathways involved in tumour necrosis factor secretion by Plasmodium falciparum-stimulated human monocytes. 782 69

The intercellular adhesion molecule (ICAM) 1 is an Ig-like cell adhesion molecule expressed by several cell types, including leukocytes and endothelial cells. It can be induced in a cell-specific manner by several cytokines, for example, tumor necrosis factor-alpha, interleukin-1, and interferon-gamma, and inhibited by glucocorticoids. Its ligands are the membrane-bound integrin receptors LFA-1 and Mac-1 on leukocytes, CD43, the soluble molecule fibrinogen, the matrix factor hyaluronan, rhinoviruses, and Plasmodium falciparum malaria-infected erythrocytes. ICAM-1 expression is predominantly transcriptionally regulated. The ICAM-1 promoter contains several enhancer elements, among them a novel kappa B element which mediates effects of 12-O-tetradecanoylphorbol-13-acetate, interleukin-1, lipopolysaccharide, tumor necrosis factor-alpha, and glucocorticoids. Expression regulation is cell specific and depends on the availability of cytokine/hormone receptors, signal transduction pathways, transcription factors, and posttranscriptional modification. ICAM-1 plays a role in inflammatory processes and in the T-cell mediated host defense system. It functions as a costimulatory molecule on antigen-presenting cells to activate MHC class II restricted T-cells, and on other cell types in association with MHC class I to activate cytotoxic T-cells. ICAM-1 on endothelium plays an important role in migration of (activated) leukocytes to sites of inflammation. ICAM-1 is shed by the cell and detected in plasma as sICAM-1. Regulation and significance of sICAM-1 are as yet unclear, but sICAM-1 is increased in many pathological conditions. ICAM-1 may play a pathogenetic role in rhinovirus infections. Derangement of ICAM-1 expression probably contributes to the clinical manifestations of a variety of diseases, predominantly by interfering with normal immune function. Among these are malignancies (e.g., melanoma and lymphomas), many inflammatory disorders (e.g., asthma and autoimmune disorders), atherosclerosis, ischemia, certain neurological disorders, and allogeneic organ transplantation. Interference with ICAM-1 leukocyte interaction using mAbs, soluble ICAM-1, antisense ICAM-1 RNA, and in the case of melanoma mAb-coupled immunotoxin, may offer therapeutic possibilities in the future. Integration of knowledge concerning membrane-bound and soluble ICAM-1 into a single functional system is likely to contribute to elucidating the immunoregulatory function of ICAM-1 and its pathophysiological significance in various disease entities.
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PMID:Intercellular adhesion molecule-1. 883 67

Molecular immunologic determinants of disease severity during Plasmodium falciparum malaria are largely undetermined. Our recent investigations showed that peripheral blood mononuclear cell (PBMC) cyclooxygenase-2 (COX-2) gene expression and plasma prostaglandin E(2) (PGE(2)) production are suppressed in children with falciparum malaria relative to healthy, malaria-exposed children with partial immunity. Furthermore, decreased COX-2/PGE(2) levels were significantly associated with increased plasma interleukin-10 (IL-10), an anti-inflammatory cytokine that inhibits the expression of COX-2 gene products. To determine the mechanism(s) responsible for COX-2-derived PGE(2) suppression, PBMCs were cultured from children with falciparum malaria. PGE(2) production was suppressed under baseline and COX-2-promoting conditions (stimulation with lipopolysaccharide [LPS] and interferon [IFN]-gamma) over prolonged periods, suggesting that an in vivo-derived product(s) was responsible for reduced PGE(2) biosynthesis. Ingestion of hemozoin (malarial pigment) by PBMC was investigated as a source of COX-2/PGE(2) suppression in PBMCs from healthy, malaria-naive adults. In addition, synthetically prepared hemozoin, beta-hematin, was used to investigate the effects of the core iron component of hemozoin, ferriprotoporphyrin-IX (FPIX). Physiologic concentrations of hemozoin or b-hematin suppressed LPS- and IFN-gamma-induced COX-2 mRNA in a time- and dose-dependent manner, resulting in decreased COX-2 protein and PGE(2) production. Suppression of COX-2/PGE(2) by hemozoin was not due to decreased cell viability as evidenced by examination of mitochondrial bioactivity. These data illustrate that ingestion of FPIX by blood mononuclear cells is responsible for suppression of COX-2/PGE(2). Although hemozoin induced overproduction of IL-10, neutralizing IL-10 antibodies failed to restore PGE(2) production. Thus, acquisition of hemozoin by blood mononuclear cells is responsible for suppression of PGE(2) in malaria through inhibition of de novo COX-2 transcripts via molecular mechanisms independent of increased IL-10 production.
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PMID:Reduced peripheral PGE2 biosynthesis in Plasmodium falciparum malaria occurs through hemozoin-induced suppression of blood mononuclear cell cyclooxygenase-2 gene expression via an interleukin-10-independent mechanism. 1550 82

Human chitotriosidase (Chit), a chitinolytic enzyme, is a member of the chitinase family. In human plasma, Chit activity has been proposed as a biochemical marker of macrophage activation in several lysosomal diseases. Recently we found that Chit activity is higher in patients affected by Plasmodium falciparum malaria infection, suggesting that Chit may reflect induction of an immunological response. To assess this hypothesis, we evaluated the CHIT1 mRNA levels in human monocytes/macrophages (HMMs) following treatment with interferon-gamma (IFNgamma), tumor necrosis factor-alpha (TNFalpha), and lipopolysaccharide (LPS). Stimulation of macrophages with INF-gamma, TNF-alpha, and LPS resulted in an increase in Chit activity as well as the levels of CHIT1 mRNA as measured by quantitative real-time PCR. The data presented in this article show that Chit plays a role in the response to the activation of INF-gamma-, TNF-alpha-, and LPS-driven macrophages, suggesting that the production of Chit by macrophages could have biological relevance in the immune-response.
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PMID:Interferon-gamma, tumor necrosis factor-alpha, and lipopolysaccharide promote chitotriosidase gene expression in human macrophages. 1590 May 64