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)

Chloroquine (CQ) is a lysosomotropic weak base with over 60 years of clinical use for the treatment of malaria and rheumatologic disorders. Consistent with its anti-inflammatory properties, CQ has been shown to interfere with TNF-alpha release from mononuclear phagocytes. Because it is unclear how CQ mediates these immunomodulatory effects, we set out to elucidate its mechanism of action. CQ exhibited dose-dependent inhibition of LPS-induced TNF-alpha release from human PBMC at therapeutically attainable concentrations. Additional studies to determine the specificity of this effect showed that although CQ reduced IL-1beta and IL-6 release, secretion of RANTES was unaffected. CQ acted by reducing TNF-alpha mRNA accumulation without destabilizing its mRNA or interfering with NF-kappaB nuclear translocation or p50/p65 isoform composition of DNA-binding complexes. Intracellular cytokine staining indicated that CQ reduced TNF-alpha production pretranslationally without interfering with TNF-alpha processing or release. We utilized bafilomycin A1 pretreatment to block the pH-dependent trapping of CQ in endosomes and lysosomes. Although bafilomycin A1 alone did not interfere with TNF-alpha expression, preincubation augmented the ability of CQ to reduce TNF-alpha mRNA levels, suggesting that CQ did not act by a lysosomotropic mechanism. Using confocal microscopy, we showed that bafilomycin A1 pretreatment resulted in a dramatic redistribution of quinacrine, a fluorescent congener of CQ, from cytoplasmic vacuoles to the nucleus. These data indicate that CQ inhibits TNF-alpha gene expression without altering translocation of NF-kappaB p50/p65 heterodimers. This dose-dependent effect occurs over a pharmacologically relevant concentration range and does not require pH-dependent lysosomotropic accumulation of CQ.
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PMID:Chloroquine interferes with lipopolysaccharide-induced TNF-alpha gene expression by a nonlysosomotropic mechanism. 1090 61

During pregnancy, a local and systemic Th2 bias of maternal immunity favors Th1-dependent infections such as malaria. This study measured cytokines secreted in cultures of chorionic villi, placental blood cells (PBC), and serum in term placentas from 88 malaria-infected and -noninfected Cameroon women. Interleukin (IL)--2 and --4 were consistently low; IL-1 beta, IL-6, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)--beta 2 were highest in villi cultures. Tumor necrosis factor (TNF)--alpha, interferon (IFN)--gamma, and IL-10 were highest in PBC cultures. Malaria placental infection increased Th1-type cytokines, whereas Th2-type cytokines and TGF-beta 2 were unchanged. Addition of lipopolysaccharide or infected erythrocytes to cultures increased TNF-alpha, IL-1 beta, IL-6, and IL-10 secretions but not those of IFN-gamma and IL-4. Overall, Plasmodium falciparum induced a placental immune response involving both Th1- and Th2-type cell activation. Although the Th1 pathway was favored, IL-10 secretion was also increased, and this increase should be effective in protecting the placenta by controlling the negative effects of Th1 cytokines on pregnancy.
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PMID:Plasmodium falciparum induces a Th1/Th2 disequilibrium, favoring the Th1-type pathway, in the human placenta. 1131 91

The balance between pro- and antiinflammatory cytokines may be important in malaria presentation and outcome. Malaria tends to be more severe in children than in adults, presumably because partial immunity develops with age. However, the full nature of, and age-related differences in, anti-malarial immunity are unknown. We compared: (1) serum and cell-specific cytokines of patients with acute malaria to those of patients with other acute illnesses and to those of healthy adults and (2) the cytokine responses of parasitemic children and parasitemic adults. Flow cytometry was done on the peripheral blood mononuclear cells of 148 hospitalized children, 161 febrile hospitalized adults, and 20 healthy adults in Malawi, Africa, a malaria-endemic country. Serum cytokines were also assessed for 80 of these patients. Thirty-eight participants were parasitemic with Plasmodium falciparum. Serum interleukin (IL)-10 (an antiinflammatory, immunoregulatory, and type 2 cytokine) levels were higher in malaria patients than in other patients (medians 502 pg/mL vs 16 pg/mL, P = 0.002), and the percentages of various lymphocyte populations making IL-6 (a proinflammatory, type 2 cytokine regulating iron distribution) were lower in malaria patients than in other patients (e.g., for spontaneous production by children's CD8(+) T cells: medians 1.4% vs 33.1%, P = 0.004). For adult patients, the percentages of lymphocytes spontaneously making IL-4 (a type 2 cytokine) were significantly lower in those with malaria than in those without malaria (medians 0.9% vs 2.1%, P = 0.005). The percentages of monocytes spontaneously making IL-8 (a chemotactic, proinflammatory chemokine) were higher in parasitemic children than in parasitemic adults (medians 5.8% vs 1.7%, P = 0.003). A number of cellular proinflammatory, type 1 parameters were significantly higher in all children (with or without malaria) than in all adults; these included the percentages of various lymphocyte populations making IL-6, both IL-6 and interferon-gamma, or IL-8. These data support the importance of IL-10 in malaria parasitemia. Given the lack of an IL-4 (type 2) response, IL-10's primary role may be immunoregulatory rather than type 2 in nature. In this study, the immune response to malaria was more proinflammatory in children than in adults. This difference, if corroborated by other studies, could be related to malaria's greater severity in children.
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PMID:Cytokines and malaria parasitemia. 1146 50

Cytokines function at the cellular, microenvironmental level, but human cytokine assessment is most commonly done at the macro level, by measuring serum cytokines. The relationships between serum and cellular cytokines, if there are any, are undefined. In a study of hospitalized patients in Malawi, we compared cytometrically assessed, cell-specific cytokine data to serum interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) levels in 16 children and 71 (IL-2, -4, -6, -10) or 159 (IL-8, IFN-gamma, and TNF-alpha) adults, using Wilcoxon rank sum tests and Pearson's (r(p)) and Spearman's (r(s)) rank correlations. For the entire study group, correlations between identical serum and cellular cytokines mainly involved IL-8 and IFN-gamma, were few, and were weakly positive (r < 0.40). Blood culture-positive persons had the most and strongest correlations, including those between serum IL-2 levels and the percentages of lymphocytes spontaneously making IL-2 (r(s) = +0.74), serum IL-8 levels and the percentages of lymphocytes spontaneously making IL-8 (r(p) = +0.66), and serum IL-10 levels and the percentages of CD8(+) T cells making TNF-alpha (r(p) = +0.89). Human immunodeficiency virus (HIV)-positive persons had the next largest number of correlations, including several serum IL-8 level correlations, correlation of serum IL-10 levels with the percentages of lymphocytes producing induced IL-10 (r(s) = +0.36), and correlation of serum IFN-gamma levels and the percentages of lymphocytes spontaneously making both IL-6 and IFN-gamma in the same cell (r(p) = +0.59). HIV-negative, malaria smear-positive, and pediatric patients had few significant correlations; for the second and third of these subgroups, serum IL-8 level was correlated with the percentage of CD8(-) T cells producing induced IL-8 (r(s) = +0.40 and r(s) = +0.56, respectively). Thus, the strength of associations between serum and cellular cytokines varied with the presence or absence of bloodstream infection, HIV status, and perhaps other factors we did not assess. These results strongly suggest that serum cytokines at best only weakly reflect peripheral blood cell cytokine production and balances.
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PMID:Comparison of serum and cell-specific cytokines in humans. 1168 46

The present study revealed no changes in the serum levels of IL-8 in malaria patients compared with controls. Such result however, does not exclude a role for IL-8 in falciparum malaria, as it is produced by activated endothelial cells that may be captured by receptors on the endothelial surface. This would allow local concentrations of IL-8 to be generated at the vessel wall without being shed into the circulation. The marked elevation of ICAM-1 and VCAM-1 in serum of falciparum malaria patients may support the concept that dysfunction of the endothelium is important in the pathophysiology of the disease. Increased level of IL-6 in serum of patients may contribute to endothelial damage and dysfunction by expression of endothelial adhesion molecules that in turn result in infected erythrocytes attraction to the endothelium and pathologic endothelial dysfunction.
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PMID:Serum levels of some cytokines and soluble adhesion molecules in normal and patients with malignant malaria in Zambia. 1177 16

Fifty subjects living in a malaria endemic area were studied at diagnosis of a Plasmodium falciparum attack and 3 weeks later. Absolute numbers of CD3(+), CD4(+) and CD8(+) lymphocytes as well as plasma cytokines and secreted cytokines after in vitro mitogenic stimulation were measured. At enrollment, lymphopenia was observed, lending support to the reallocation hypothesis during the acute phase. A significant elevation of the number of CD8(+) cells was present in the peripheral blood during the recovery phase. During the acute phase, plasma IL-6 levels peaked while in vitro production capacity was high at both phases. Plasma IL-6 concentrations were positively related to blood parasite density at D0, as IL-4 and IFN-gamma, suggesting an early intervention of these cytokines. Plasma IL-2 levels were low at diagnosis although cells retained their ability to produce IL-2, which was found more frequently in plasma after cure. Acquisition of immunity with age was in relation with greater secretion abilities of cells for type 1 and type 2 cytokines during the parasite clearance phase. We conclude to an early implication of type 2 cytokines and IFN-gamma, with particularly high levels of IL-6.
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PMID:Plasma and in vitro levels of cytokines during and after a Plasmodium falciparum malaria attack in Gabon. 1220 92

Cytokines regulate cellular immune activity and are produced by a variety of cells, especially lymphocytes, monocytes, and macrophages. Multiparameter flow cytometry is often used to examine cell-specific cytokine production after in vitro phorbol 12-myristate 13-acetate and ionomycin induction, with brefeldin A or other agents added to inhibit protein secretion. Spontaneous ex vivo production reportedly rarely occurs. We examined the spontaneous production of interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) by peripheral-blood B lymphocytes, T cells, CD8(-) T cells, CD8(+) T cells, CD3(-) CD16/56(+) lymphocytes (natural killer [NK] cells), CD3(+) CD16/56(+) lymphocytes (natural T [NT] cells), and/or monocytes of 316 acutely ill hospitalized persons and 62 healthy adults in Malawi, Africa. We also evaluated the relationship between spontaneous and induced cytokine production. In patients, spontaneous TNF-alpha production occurred most frequently, followed in descending order by IFN-gamma, IL-8, IL-4, IL-10, IL-6, and IL-2. Various cells of 60 patients spontaneously produced TNF-alpha; for 12 of these patients, TNF-alpha was the only cytokine produced spontaneously. Spontaneous cytokine production was most frequent in the immunoregulatory cells, NK and NT. For IL-2, IL-4, IL-6, IL-8, and IL-10, spontaneous cytokine production was associated with greater induced production. For TNF-alpha and IFN-gamma, the relationships varied by cell type. For healthy adults, IL-6 was the cytokine most often produced spontaneously. Spontaneous cytokine production was not unusual in these acutely ill and healthy persons living in an area where human immunodeficiency virus, mycobacterial, malaria, and assorted parasitic infections are endemic. In such populations, spontaneous, as well as induced, cell-specific cytokine production should be measured and evaluated in relation to various disease states.
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PMID:Spontaneous cytokine production and its effect on induced production. 1220 58

The intensity of malaria transmission is related to the pattern of malarial disease observed in different regions, but populations may also differ in their underlying predispositions to severe malarial anemia or cerebral malaria. In western Kenya, where severe malarial anemia is much more common than cerebral malaria, the distributions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, transforming growth factor (TGF)-beta, IL-6, and interferon (IFN)-gamma alleles were examined in a cohort of young men. The cohort displayed a marked bias toward genotypes associated with low expression of IFN-gamma and IL-6, cytokines that, at high levels, have been implicated in malarial anemia and poor malaria outcomes. By contrast, the frequency of the TNF-alpha -238A allele, which has been associated with severe malarial anemia, was found to be similar to the frequency previously reported in comparison populations in Africa and elsewhere. IFN-gamma and IL-6 genotypes may play roles in the development of severe malaria and could contribute to the relative frequency of severe malarial anemia or cerebral malaria in exposed populations.
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PMID:Profound bias in interferon-gamma and interleukin-6 allele frequencies in western Kenya, where severe malarial anemia is common in children. 1223 42

Non-human primates could prove to be suitable models for the study of infectious diseases such as malaria, tuberculosis, and hepatitis; the molecules of their immune systems are in the process of being fully characterized. Due to the relevance of cytokines in the modulation of the immune response, a molecular analysis of these proteins in non-human primates from the Aotus genus was carried out. Peripheral blood mononuclear cells from four species of Aotusmonkey were obtained and their mRNAs for interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-gamma (IFN), and tumor necrosis factor (TNF)-alpha were characterized. This study shows a high degree of conservation between nucleotide and amino acid sequences of cytokines from different Aotus species and those from humans. The TNF-alpha molecules were identical in amino acid sequences for both.
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PMID:Identification, cloning, and sequencing of different cytokine genes in four species of owl monkey. 1246 97

Human immunodeficiency virus (HIV) infection is the primary cause of morbidity and mortality in Malawi, Africa, because of its many effects on the immune system. Immune cells communicate through cytokines; therefore, we examined the relationships between HIV serostatus and cell-specific cytokine production for 40 asymptomatic, employed adults and 312 acutely ill, hospitalized patients in Malawi. We also measured the plasma HIV-1 RNA levels of 13 asymptomatic persons and 83 patients found to be HIV(+). We incubated peripheral whole blood with brefeldin-A +/- phorbol 12-myristate 13-acetate and ionomycin and then permeabilized, fixed, fluorescently stained, and examined the mononuclear cells with four-color, six-parameter flow cytometry. The percentage of lymphocytes expressing CD4 did not differ significantly between the HIV(+) and HIV(-) healthy adults (medians, 35.2 vs. 40.8%, respectively), but a wide array of cytokine parameters were lower in the HIV(+) than in the HIV(-) asymptomatic persons, for example, median percentages of T cells producing induced interleukin 2 (IL-2) (8.7 vs. 16.5%, respectively) and spontaneously producing IL-6 (0.7 vs. 11.0%, respectively). Also, four T cell parameters reflecting type 2-to-type 1 cytokine balances (T2/T1) were higher in the HIV(+), versus HIV(-), asymptomatic persons. Unlike the healthy adults, for patients with mycobacteremia/fungemia or malaria, the HIV(+) patients had higher median percentages of T cells and CD8(+) T cells producing induced interferon gamma than did the HIV(-) PATIENTS: For both asymptomatic and acutely ill persons, HIV-1 plasma levels were positively correlated with T2/T1 parameters. Cell-specific cytokine effects of HIV infection may precede measurable effects on CD4 expression. Cytokine therapies, even beyond periodic administration of IL-2, may improve the responses of HIV-infected persons to both HIV and coinfections.
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PMID:Peripheral blood cell-specific cytokines in persons with untreated HIV infection in Malawi, Africa. 1248 8


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