Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anemia associated with malaria is complex, and multiple factors contribute to its severity. An increased destruction and a decreased production of erythrocytes are involved; however, the mechanisms responsible remain unclear. Tumor necrosis factor alpha (TNF-alpha), released by macrophages in response to infection, is thought to play a role through its ability to inhibit erythropoiesis. In these studies we have examined erythropoiesis in mice infected with Plasmodium berghei and in mice infused with recombinant TNF-alpha via implanted osmotic pumps. In both groups of mice there was (i) a reduction of pluripotent stem cells in the bone marrow and a concomitant increase in the spleen, (ii) a reduction of erythroid progenitor cells, and (iii) a reduced incorporation of 59Fe into erythrocytes. When P. berghei-infected mice were given antiserum against recombinant murine TNF, erythropoiesis was partially restored. There was a significant increase in bone marrow stem cells, erythroid progenitor cells, and 59Fe incorporation into erythrocytes in P. berghei-infected mice that had been treated with anti-TNF. How TNF may act, directly or indirectly, to inhibit erythropoiesis is not yet clear. These results demonstrate that TNF mediates, in part, the anemia associated with malaria.
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PMID:Tumor necrosis factor alpha and the anemia associated with murine malaria. 270 58

Cytokines are now recognized to play important roles in the physiology of the central nervous system (CNS) during health and disease. Tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of several human CNS disorders including multiple sclerosis, AIDS dementia, and cerebral malaria. We have generated transgenic mice that constitutively express a murine TNF-alpha transgene, under the control of its own promoter, specifically in their CNS and that spontaneously develop a chronic inflammatory demyelinating disease with 100% penetrance from around 3-8 weeks of age. High-level expression of the transgene was seen in neurons distributed throughout the brain. Disease is manifested by ataxia, seizures, and paresis and leads to early death. Histopathological analysis revealed infiltration of the meninges and CNS parenchyma by CD4+ and CD8+ T lymphocytes, widespread reactive astrocytosis and microgliosis, and focal demyelination. The direct action of TNF-alpha in the pathogenesis of this disease was confirmed by peripheral administration of a neutralizing anti-murine TNF-alpha antibody. This treatment completely prevented the development of neurological symptoms, T-cell infiltration into the CNS parenchyma, astrocytosis, and demyelination, and greatly reduced the severity of reactive microgliosis. These results demonstrate that overexpression of TNF-alpha in the CNS can cause abnormalities in nervous system structure and function. The disease induced in TNF-alpha transgenic mice shows clinical and histopathological features characteristic of inflammatory demyelinating CNS disorders in humans, and these mice represent a relevant in vivo model for their further study.
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PMID:Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. 747 82

Tumor necrosis factor alpha (TNF alpha) is a central mediator of the immunological response and the location of the gene within the major histocompatibility complex (MHC) has prompted much speculation about the role of TNF alpha alleles in inflammatory and MHC-associated autoimmune diseases. A G to A transition polymorphism at position -308 of the TNF alpha promoter/enhancer region has been described. The uncommon -308A allele was shown to be strongly associated with human leukocyte antigen (HLA)-DR3, known to be related to a TNF alpha "high producer" phenotype. In support for a clinical relevance, the -308A allele is implicated in susceptibility for cerebral malaria. In this study, we determined the junctional consequences of the TNF -308 polymorphism. Therefore, we analyzed both allelic forms (TNF alpha(-308G) and TNF alpha(-3O8A)) of the TNF alpha enhancer/promoter region (-598/+108) in a transient transfection system, using chloramphenicol acetyltransferase (CAT) as reporter gene. The T cell line Jurkat and the B cell line Raji served as hosts in these experiments. The results showed no differences in the level of inducible reporter gene expression between the TNF(-3O8G)/CAT and the TNF(-308A)/CAT constructs. These data were confirmed by allele specific TNF alpha transcript quantification (ASTQ) analysis, which demonstrated that both TNF alleles contribute equally to the total amount of mRNA in peripheral blood mononuclear cells (PBMCs) stimulated with phorbol 12-myristate 13-acetate (PMA)/anti-CD3. In analogy, no difference between the level of transcription of the -308A and -308G alleles was observed in lipopolysaccharide (LPS)-stimulated peripheral blood monocytes. This study indicates that the TNF alpha -308 G to A transition is not responsible for differential TNF alpha production induced by standard in vitro stimuli.
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PMID:Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. 883 66

Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.
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PMID:Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. 909 69

Tumor necrosis factor alpha (TNFalpha), an early cytokine produced by activated macrophages, plays an essential role in normal and pathological inflammatory reactions. The excessive production of TNFalpha is prevented by the so-called "macrophage-deactivating factors." This study examines the role of two structurally related neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating peptide (PACAP), as inhibitors of TNFalpha. Both VIP and PACAP inhibit TNFalpha production from lipopolysaccharide-stimulated RAW 246.7 cells in a dose- and time-dependent manner. Although the activated cells express mRNA for all three VIP/PACAP receptors, agonist and antagonist studies indicate that the major receptor involved is VIP1R. VIP/PACAP inhibit TNFalpha gene expression by affecting both NF-kB binding and the composition of the cAMP responsive element binding complex (CREB/c-Jun). Two transduction pathways, a cAMP-dependent and a cAMP-independent pathway, are involved in the inhibition of TNFalpha gene expression and appear to differentially regulate the transcriptional factors involved. Because TNFalpha plays a central role in various inflammatory diseases such as endotoxic shock, multiple sclerosis, cerebral malaria, and various autoimmune conditions, the down-regulatory effect of VIP/PACAP may have a significant therapeutic potential.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun. 981 54

Tumor necrosis factor alpha (TNF-alpha) is associated with malarial pathology in both humans and mice. In Plasmodium chabaudi chabaudi (AS) infections, the production of TNF-alpha and reactive metabolites from macrophages are also thought to play a role in controlling acute parasitemia. Since many of the biological functions of TNF-alpha are effected through the p55 receptor (p55R), mice made defective in this receptor via a targeted gene disruption (p55R(-/-)) have been used to study its involvement in the immune response against P. chabaudi chabaudi and in the pathology associated with this infection. In the absence of the p55R, mice could overcome their primary infection, although higher acute-blood-stage parasitemias and more significant recrudescences were observed. Hypoglycemia, hypothermia, loss of erythrocytes, and loss of body weight, which occur transiently in this infection, were exacerbated by the lack of the p55R, but the differences were small, suggesting that other factors affect these symptoms. In contrast to wild-type (WT) mice, a second challenge infection in p55R(-/-) mice resulted in a course of infection similar to a primary infection. The malaria-specific immunoglobulin G antibody response of p55R(-/-) mice was lower than that of WT mice and was not increased by the second challenge infection. These data suggest that p55R(-/-) mice do not develop an efficient memory B-cell response against malarial infection and that this antibody response is important in immunity to reinfection.
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PMID:Tumor necrosis factor alpha p55 receptor is important for development of memory responses to blood-stage malaria infection. 1099 77

Tumor necrosis factor alpha (TNF alpha) is thought to be a critical mediator of malaria fever, and mild malaria was previously reported to be linked to the MHC region containing the tumor necrosis factor alpha gene (TNF). Thirty-four families from Burkina Faso were analyzed to test for linkage between polymorphisms within the MHC region and mild malaria using the maximum-likelihood-binomial (MLB) program. Two-point analysis indicated linkage of mild malaria to TNFd (LOD = 3.27; P = 5.44 x 10(-5)). Using multipoint analysis, we also found evidence for linkage of mild malaria to the MHC region, with a peak close to TNF (LOD = 3.86; P = 1.22 x 10(-5)). Our results support genes within the MHC region being involved in mild malaria. In particular, the genetic variation within TNF may influence susceptibility to mild malaria. Nevertheless, TNF-238, TNF-244 and TNF-308 polymorphisms are unlikely to explain linkage of mild malaria to the MHC region, and the causal mutations remain to be identified.
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PMID:Linkage of mild malaria to the major histocompatibility complex in families living in Burkina Faso. 1256 84

Tumor necrosis factor alpha(TNFalpha) is a crucial mediator involved in the communications between immune and nervous systems in physiological conditions, and its relevance is amplified during disease. Considered originally detrimental and a target for therapeutic intervention, recently it has also gained attention for its protective role, especially in central nervous system (CNS) confined diseases. Thus, TNFalpha has become the key molecule illustrating the peculiar and still not completely understood pathways by which inflammatory and immune reactions occur in the brain. Several human pathologies that lack an efficient therapy and that carry enormous social costs rely on these mechanisms. Thus, further research is needed to improve our knowledge and to allow the identification of therapeutic targets or strategies for immune-mediated inflammatory disease of the CNS in which TNFalpha is primarily involved. We describe here how to induce experimental autoimmune encephalomyelitis, cerebral malaria, and brain ischemia in rodents, and some protocols to analyze them. The application of innovative research strategies or original therapeutic approaches to these experimental models may be rewarding in terms of advancement in a field that is crucial for the management of many human patients.
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PMID:TNFalpha in experimental diseases of the CNS. 1506 39

Tumor necrosis factor alpha (Tnf) plays a pleiotropic role in murine malaria. Some investigations have correlated Tnf with hypothermia, hyperlactatemia, hypoglycemia, and a suppression of the erythropoietic response, although others have not. In this study, we have evaluated parasitemia, survival rate and several pathological features in C57BL/6JTnf(-/-) and C57BL/6JTnf(+/+) mice after infection with Plasmodium chabaudi adami 408XZ. Compared to the C57BL/6JTnf(+/+) mice, C57BL/6JTnf(-/-) mice showed increased parasitemia and decreased survival rate, whereas blood glucose, blood lactate and body weight were not significantly different. However, C57BL/6JTnf(-/-) mice suffered significantly more from severe anemia and hypothermia than C57BL/6JTnf(+/+) mice. These results suggest that Tnf is an important mediator of parasite control, but not of anemia development. We hypothesize that the high mortality observed in the Tnf knock-out mice is due to increased anemia and pathology as a direct result of increased levels of parasitemia.
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PMID:Pathology of Tnf-deficient mice infected with Plasmodium chabaudi adami 408XZ. 1671 3

Hepatosplenomegaly among Kenyan schoolchildren has been shown to be exacerbated where there is transmission of both Schistosoma mansoni and Plasmodium falciparum. This highly prevalent and chronic morbidity often occurs in the absence of ultrasound-detectable periportal fibrosis and may be due to immunological inflammation. For a cohort of school-age children, whole-blood cultures were stimulated with S. mansoni soluble egg antigen (SEA) or soluble worm antigen (SWA). Responses to SWA were found to be predominantly Th2 cytokines; however, they were not significantly associated with either hepatosplenomegaly or infection with S. mansoni or P. falciparum. In comparison, SEA-specific Th2 cytokine responses were low, and the levels were negatively correlated with S. mansoni infection intensities and were lower among children who were coinfected with P. falciparum. Tumor necrosis factor alpha levels in response to stimulation with SEA were high, and a negative association between presentation with hepatomegaly and the levels of the regulatory cytokines interleukin-6 and transforming growth factor beta(1) suggests that a possible mechanism for childhood hepatomegaly in areas where both malaria and schistosomiasis are endemic is poor regulation of an inflammatory response to schistosome eggs.
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PMID:Hepatosplenomegaly is associated with low regulatory and Th2 responses to schistosome antigens in childhood schistosomiasis and malaria coinfection. 1828 96


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