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Journal ArticleDOI

Putative pathophysiological interactions of cytokines and phagocytic cells in severe human falciparum malaria

01 Jul 1994-Clinical Infectious Diseases (Oxford University Press)-Vol. 19, Iss: 1, pp 117-131
TL;DR: The putative mechanisms by which cytokines may mediate both beneficial and deleterious effects by activating phagocytic cells in severe falciparum malaria are discussed.
Abstract: The severe disease and high mortality associated with Plasmodium falciparum infection have traditionally been attributed solely to parasitic virulence factors, but more recent evidence suggests that the host's immunologic response may also contribute to the pathophysiology of the disease in humans. This response would be expected to be proportionate--in intensity and nature--to the antigenic load created by the sequestration of parasites in the microvasculature and to be directed against the sites of maximal parasitization; thus the immunologic response could potentially contribute to the pathophysiology of both survival and fatal outcome in severe infection. Cytokines appear to play a pivotal role in the activation of the immune response in human falciparum malaria, and their levels correlate with disease severity. The putative mechanisms by which cytokines may mediate both beneficial and deleterious effects by activating phagocytic cells in severe falciparum malaria are discussed.
Citations
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Journal ArticleDOI
TL;DR: The complex relationships between inflammatory cytokines and disease in P. falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, are illustrated.
Abstract: Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, 500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = 5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.

405 citations


Cites background from "Putative pathophysiological interac..."

  • ...IL-6 is an important proinflammatory cytokine that is upregulated by TNF- and acts in concert with other inflammatory mediators to control parasitemia (18, 48)....

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  • ...Elevated TNF- , produced mainly by blood monocytes and tissue macrophages, has been shown to correlate with disease severity in multiple studies (5, 8, 18, 19, 48)....

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Journal ArticleDOI
01 Nov 2000-Blood
TL;DR: CD36-dependent binding and signaling appears to be crucial for the nonopsonic clearance of PEs and does not appear to contribute to the increase in TNF-alpha that is prognostic of poor outcome in clinical malaria.

272 citations

Journal ArticleDOI
TL;DR: The Tissue Factor Model (TFM) for malaria pathogenesis is presented, which places TF as the interface between sequestration, endothelial cell (EC) activation, blood coagulation disorder, and inflammation often associated with the disease.
Abstract: Malaria remains a highly prevalent disease in more than 90 countries and accounts for at least 1 million deaths every year. Plasmodium falciparum infection is often associated with a procoagulant t...

161 citations


Cites background from "Putative pathophysiological interac..."

  • ...Of note, some reports have linked cytokine levels to disease severity and complications [56,57,64,68–71]....

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Journal ArticleDOI
TL;DR: It was only in 1880 that Charles Laveran, a French physician working in Algeria, discovered the true causative agent as being a sporozoan of the genus Plasmodium, and to map the malaria genome, identifying a huge number of genes located on 14 chromosomes.
Abstract: Malaria is an Italian word composed of “ mala ” and “ aria,” derived from malus (bad), and aeris (air). It was first used to describe a fever (miasma), which was wrongly attributed to exposure to poisonous air rising from marshes. Although the disease had been described in the Hippocratic Collection (460 to 377 BC) and its relation to mosquitoes suggested in the 5th century AD, by the Indian physician Susruta, it was only in 1880 that Charles Laveran, a French physician working in Algeria, discovered the true causative agent as being a sporozoan of the genus Plasmodium. More than a century later, we got to map the malaria genome, identifying a huge number of genes located on 14 chromosomes. Malaria is acquired through the sting of an infected Anopheles mosquito, which injects the sporozoites into the host’s dermis. These are carried with the blood stream to the liver, where they mature in the hepatocytes (extra-erythrocytic cycle) to tissue schizonts that release their merozoites into the hepatic sinusoids. The latter invade the red cells, starting the erythrocytic cycle, which comprises ring forms, trophozoites, and, subsequently, schizonts that contain a new generation of merozoites. The parasitized cells are induced by plasmodial DNA to develop a microtubular system that conveys nutrients to the parasite. They eventually rupture and release the merozoites, which repeat the same cycle. A few merozoites are sexually differentiated into male and female gametocytes, which are essential for the completion of the sexual cycle in the vector.

159 citations


Cites background from "Putative pathophysiological interac..."

  • ...The latter secrete interfer on-g, which amplifies the monocyte response by a positive feed back mechanism (20)....

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Journal ArticleDOI
TL;DR: The molecular mechanisms underlying HZ-inducible macrophage (Mφ) chemokine mRNA expression are investigated to better understand the molecular mechanisms through which parasite components, such as HZ, modulate the immune response during malaria infection.
Abstract: Chemokine production has been associated with the immunopathology related to malaria. Previous findings indicated that hemozoin (HZ), a parasite metabolite released during schizogeny, might be an important source of these proinflammatory mediators. In this study we investigated the molecular mechanisms underlying HZ-inducible macrophage (Mφ) chemokine mRNA expression. We found that both Plasmodium falciparum HZ and synthetic HZ increase mRNA levels of various chemokine transcripts (MIP-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2, and MCP-1/CCL2) in murine B10R Mφ. The cellular response to HZ involved ERK1/2 phosphorylation, NF-κB activation, reactive oxygen species (ROS) generation, and ROS-dependent protein-tyrosine phosphatase down-regulation. Selective inhibition of either IκBα or the ERK1/2 pathway abolished both NF-κB activation and chemokine up-regulation. Similarly, blockage of HZ-inducible Mφ ROS with superoxide dismutase suppressed chemokine induction, strongly reduced NF-κB activation, and restored HZ-mediated Mφ protein-tyrosine phosphatase inactivation. In contrast, superoxide dismutase had no effect on EKR1/2 phosphorylation by HZ. Collectively, these data indicate that HZ triggers ROS-dependent and -independent signals, leading to increased chemokine mRNA expression in Mφ. Overall, our findings may help to better understand the molecular mechanisms through which parasite components, such as HZ, modulate the immune response during malaria infection.

136 citations


Cites background from "Putative pathophysiological interac..."

  • ...Discussion In Pf malaria, M have been proposed as one of the main sources of proinflammatory mediators (2); therefore, it is of paramount importance to identify the parasite components participating in chemokine induction and to define the underlying regulatory mechanisms....

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  • ..., proinflammatory cytokines and chemokines) also participates in malaria pathophysiology, including tissue cell damage, microvascular obstruction, severe anemia, and cerebral malaria (2)....

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  • ...M have been identified as one of the main sources of proinflammatory mediators in response to Pf infection (2)....

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References
More filters
Journal ArticleDOI
TL;DR: It has been shown that CSa, formylmethionyl peptides, PAF, and LTB4 act via unrelated receptors, suggesting that neutrophil recruitment can result from the concerted action of multiple stimuli.
Abstract: Introduction Neutrophil accumulation in a tissue is characteristic of inflammation and is observed in a variety of pathological conditions as disparate as infection, trauma, ischemia, and cancer. The process of tissue infiltration is best understood in bacterial infection, where neutrophils are selectively attracted in large numbers to phagocytose and kill the invaders. In other conditions neutrophils are presumably recruited as scavengers of damaged tissue or unwanted extracellular deposits like immune complexes or fibrin. Phagocytosis is accompanied by the release of granule enzymes, superoxide, H202, and a variety of bioactive lipids. Several of these products are required for the killing and digestion of microorganisms. They also induce inflammation and tissue damage, however, which is normally observed after neutrophil accumulation. Several neutrophil chemoattractants have been characterized in recent years; the best known are the anaphylatoxin C5a (1), formylmethionyl peptides of bacterial origin (2), plateletactivating factor (PAF; 3),1 and leukotriene B4 (LTB4; 4). These stimuli have different origins and modes of formation, and their occurrence in disease must thus be expected to vary in accord with the underlying pathophysiological process. C5a is formed upon complement activation via the classical pathway after interaction of microorganisms with antibodies or the formation of immune complexes, or via the alternative pathway after the nonimmune recognition of foreign materials. In bacterial infections, on the other hand, formylmethionyl peptides (which are released by the microorganisms) are likely to be the major attractants. PAFand LTB4 are of special interest because they can be generated by the neutrophils themselves and may thus function as autoor paracrine amplifiers of the responses elicited by other stimuli (5). It has been shown that CSa, formylmethionyl peptides, PAF, and LTB4 act via unrelated receptors, suggesting that neutrophil recruitment can result from the concerted action of multiple stimuli.

1,966 citations

Journal ArticleDOI

1,873 citations


"Putative pathophysiological interac..." refers background in this paper

  • ...Experimental evidence suggests that peripheral-blood monocytes and neutrophils release cytokines after stimulation [38-43, 46, 54] (e....

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  • ...IL-6 is synthesized by stimulated macrophages and peripheral-blood monocytes; by cytokine (TNF and IL-1)stimulated endothelial, fibroblast, and epithelial cells; by TNF-stimulated neutrophils, microglia, and astrocytes; and by B and T cell lines [50-54]....

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  • ..., IL-1, IL-6, and IL-8) from stromal cells such as hepatocytes, endothelial cells, and fibroblasts in vitro [41-43, 47, 48, 53, 54, 85], and the elevated levels of TNF and IL-1 encoun-...

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Journal ArticleDOI
20 Jun 1985-Nature
TL;DR: Two distinct but distantly related complementary DNAs encoding proteins sharing human interleukin-1 (IL-1) activity (termed IL-lα and IL-1β), were isolated from a macrophage cDNA library.
Abstract: Two distinct but distantly related complementary DNAs encoding proteins sharing human interleukin-1 (IL-1) activity (termed IL-1 alpha and IL-1 beta), were isolated from a macrophage cDNA library. The primary translation products of the genes are 271 and 269 amino acids long, although expression in Escherichia coli of the carboxy-terminal 159 and 153 amino acids produces IL-1 biological activity.

1,630 citations

Journal ArticleDOI
TL;DR: IL 1 is a highly inflammatory molecule and stimulates the production of arachidonic acid metabolites and acts synergistically with other cytokines, particularly tumor necrosis factor.
Abstract: Interleukin 1 (IL 1) is a polypeptide that is produced after infection, injury, or antigenic challenge. Although the macrophage is a primary source of IL 1, epidermal, epithelial, lymphoid, and vascular tissues synthesize IL 1. When IL 1 gains access to the circulation, it acts like a hormone and induces a broad spectrum of systemic changes in neurological, metabolic, hematologic, and endocrinologic systems. Some of the IL 1 that is synthesized remains associated with the plasma membrane and induces changes in local tissues without producing systemic responses. IL 1 affects mesenchymal tissue remodeling where it contributes to both destructive and repair processes. IL 1 activates lymphocytes and plays an important role in the initiation of the immune response. Receptors for IL 1 have been identified, but receptors are scarce and their affinities often do not match the potency of the biological response. The most consistent property of IL 1 is up-regulation of cellular metabolism and increased expression of several genes coding for biologically active molecules. IL 1 is a highly inflammatory molecule and stimulates the production of arachidonic acid metabolites. IL 1 also acts synergistically with other cytokines, particularly tumor necrosis factor. The multitude of biological responses to IL 1 is an example of the rapid adaptive changes that take place to increase the host's defensive mechanisms.

1,532 citations

Journal Article
TL;DR: The authors used the quantitative binding of murine monoclonal antibodies to the surface of cultured human umbilical vein endothelial (HUVE) cells to study the responses of HUVE cells to three different immune mediators: interleukin 1 (IL 1), tumor necrosis factor (TNF), and immune interferon (IFN-gamma) antigens.
Abstract: We have used the quantitative binding of murine monoclonal antibodies to the surface of cultured human umbilical vein endothelial (HUVE) cells to study the responses of HUVE cells to three different immune mediators: interleukin 1 (IL 1), tumor necrosis factor (TNF), and immune interferon (IFN-gamma) Antibody H4/18, reactive with an endothelial cell-specific activation antigen, does not bind to unstimulated HUVE cells but shows rapidly and transiently inducible binding (peak 4 to 6 hr) to cells stimulated by IL 1 or TNF that declines to basal levels by 24 hr, even in the continued presence of mediator Binding of H4/18 is unaffected by IFN-gamma Antibody RR1/1, reactive with intercellular adhesion molecule 1, binds to unstimulated HUVE cells, but binding is rapidly increased (plateau 24 hr) after stimulation by IL 1 or TNF and slowly increased (over several days) by IFN-gamma In contrast to H4/18 binding, the increase in RR1/1 binding is sustained in the continued presence of mediator Antibody W6/32, reactive with HLA-A,B antigens, binds to unstimulated HUVE cells and shows gradually progressive increases (over several days) in binding upon treatment with IFN-gamma or TNF These observations demonstrate that HUVE cells show distinct but overlapping patterns of antigenic modulation in response to three different lymphokines, and suggest that the "activation" of endothelial cells observed in situ may represent a complex integration of several lymphokine-mediated signals

1,424 citations


"Putative pathophysiological interac..." refers background in this paper

  • ...TNF-a induces fever [86], acute-phase protein production [87], neutrophil activation [88, 89], endothelial leukocyte adhesion molecule 1 expression [90], and lymphocyte proliferation [91] and leads to the production of IL-1 and to the production of IL-8 (a potent neutrophil chemotaxin) by macrophages, monocytes, and endothelial cells [92, 93]....

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