Elevated levels of soluble CD14 in serum of patients with acute <i>Plasmodium falciparum</i> malaria

Wenisch, Christoph; Wenisch, H J; Parschalk, Bernhard; Vanijanonta, S; Burgmann, Heinz; Exner, Markus; Zedwitz-Liebenstein, Konstantin; Thalhammer, Florian; Georgopoulos, A.; Graninger, Wolfgang; Looareesuwan, S

doi:10.1046/j.1365-2249.1996.d01-723.x

Cited by 32 publications

(26 citation statements)

References 37 publications

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“…Consistent with these findings, CD14 knockout mice were found to be at least 10-fold more resistant to LPS-induced shock than wildtype controls (13). In addition, inflammatory infectious diseases such as atopic dermatitis (14), HIV infection (15), and malaria (16), as well as extensive tissue damage in polytrauma and severe burns (17), are marked by elevated sCD14 in the circulation.…”

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confidence: 61%

A Common Single Nucleotide Polymorphism in the CD14 Promoter Decreases the Affinity of Sp Protein Binding and Enhances Transcriptional Activity

LeVan

Bloom

Bailey

et al. 2001

The Journal of Immunology

312

228

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CD14 is a pattern recognition receptor that plays a central role in innate immunity through recognition of bacterial lipoglycans, primarily LPS. Recently, our group has identified a common single nucleotide polymorphism, −159C→T, in the CD14 proximal promoter. Homozygous carriers of the T allele have a significant increase in soluble CD14, but a decreased total serum IgE. This epidemiologic evidence led us to investigate the molecular basis for the effects of CD14/−159C→T on CD14 regulation in monocytes and hepatocytes, the two major cell types known to express this gene in vivo. EMSA analysis showed that the T allele results in decreased affinity of DNA/protein interactions at a GC box that contains a binding site for Sp1, Sp2, and Sp3 transcription factors. In reporter assays, the transcriptional activity of the T allele was increased in monocytic Mono Mac 6 cells, which express low levels of Sp3, a member of the Sp family with inhibitory potential relative to activating Sp1 and Sp2. By contrast, both alleles were transcribed equivalently in Sp3-rich hepatocytic HepG2 cells. Our data indicate that the interplay between CD14 promoter affinity and the [Sp3]:[Sp1 + Sp2] ratio plays a critical mechanistic role in regulating transcription of the two CD14 alleles. Variation in a key gene of innate immunity may be important for the pathogenesis of allergy and inflammatory disease through gene-by-gene and/or gene-by-environment interactions.

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confidence: 61%

A Common Single Nucleotide Polymorphism in the CD14 Promoter Decreases the Affinity of Sp Protein Binding and Enhances Transcriptional Activity

LeVan

Bloom

Bailey

et al. 2001

The Journal of Immunology

312

228

View full text Add to dashboard Cite

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“…Similarly, experimental manipulation of circulating levels of this cytokine in mice by injection of recombinant TGF-β1 or via antibody neutralization indicated that high early or low late TGF-β1 levels were associated with uncontrolled parasitemia and increased pathology (Tsutsui andKamiyama, 1999 andreviewed in Omer et al, 2000). Two studies of natural infection in patients in Gabon (Perkins et al, 2000) and Thailand (Wenisch et al, 1995) and one study of experimental human infection (Walther et al, 2005 andWalther et al, 2006) corroborate these animal studies. Specifically, severe late-stage infection was associated with significantly reduced serum levels of TGF-β1 (7.6 pg/ml, Perkins et al, 2000;14 pg/ml, Wenisch et al, 1995) relative to levels in healthy controls (16 pg/ml, Perkins et al, 2000;63 pg/ml, Wenisch et al, 1995), suggesting that uncontrolled immunopathology exacerbated clinical disease.…”

Section: Introductionmentioning

confidence: 69%

Low levels of mammalian TGF-β1 are protective against malaria parasite infection, a paradox clarified in the mosquito host

Luckhart

Lieber

Singh

et al. 2008

Experimental Parasitology

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Nitric oxide (NO), derived from catalysis of inducible NO synthase (iNOS), limits malaria parasite growth in mammals. Transforming growth factor (TGF)-β1 suppresses iNOS in cells in vitro as well as in vivo in mice, but paradoxically severe malaria in humans is associated with low levels of TGF-β1. We hypothesized that this paradox is a universal feature of infection and occurs in the mosquito Anopheles stephensi, an invertebrate host for Plasmodium that also regulates parasite development with inducible NO synthase (AsNOS). We show that exogenous human TGF-β1 dose-dependently regulates mosquito AsNOS expression and that parasite killing by low dose TGF-β1 depends on AsNOS catalysis. Furthermore, induction of AsNOS expression by TGF-β1 is regulated by NO synthesis. These results suggest that TGF-β1 plays similar roles during parasite infection in mammals and mosquitoes and that this role is linked to the effects of TGF-β1 on inducible NO synthesis. .

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“…3E). These results are interpreted as strong evidence that, in MC, cytokine induction by R-form LPS and lipid A is independent of CD14 under physiological conditions.Enhanced levels of sCD14 render MC responsive to S-form LPS sCD14 levels are strongly up-regulated under inflammatory conditions in both humans and mice [37][38][39][40][41][42][43][44]. Therefore, we investigated also the effects of high concentrations of sCD14 (4 lg/mL recombinant sCD14) on the IL-6 production of MC in response to different amounts of Re-form and S-form LPS (Fig.…”

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confidence: 99%

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

et al. 2006

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Lipopolysaccharide (endotoxin, LPS) is a major recognition marker for the detection of gram-negative bacteria by the host and a powerful initiator of the inflammatory response to infection. Using S-and R-form LPS from wild-type and R-mutants of Salmonella and E. coli, we show that R-form LPS readily activates mouse cells expressing the signaling receptor Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), while the S-form requires further the help of the LPS-binding proteins CD14 and LBP, which limits its activating capacity. Therefore, the R-form LPS under physiological conditions recruits a larger spectrum of cells in endotoxic reactions than S-form LPS. We also show that soluble CD14 at high concentrations enables CD14-negative cells to respond to S-form LPS. The presented in vitro data are corroborated by an in vivo study measuring TNF-a levels in response to injection of R-and S-form LPS in mice. Since the R-form LPS constitutes ubiquitously part of the total LPS present in all wild-type bacteria its contribution to the innate immune response and pathophysiology of infection is much higher than anticipated during the last half century.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35593_pdf IntroductionThe interaction of highly conserved microbial constituents with the innate immune system forms the basis of recognition of and reaction against intruding pathogens in mammals. One such constituent is lipopolysaccharide (endotoxin, LPS), a major recognition marker common to gram-negative bacteria [1][2][3], a large group comprising important human pathogens as well as commensals. Thus, the interaction of LPS with cells of the innate immune system leads to the formation and release of endogenous mediators initiating inflammatory and immune responses essential for an antibacterial defense [3,4]. This primarily protective mechanism may become overshadowed by an acute pathophysiological response with the typical clinical symptoms of septic shock that frequently follows the release of inflammatory mediators, such as tumor necrosis factor (TNF)-a during infection [5][6][7].Innate immunity * Both authors contributed equally to this work. [10]. Binding of allergen to its specific IgE on the surface of MC results in an immediate release of preformed pro-inflammatory mediators (e.g., histamine, TNF-a and proteases) from cytoplasmic granules (degranulation) [11] and a later release of de novo synthesized arachidonic acid metabolites and various cytokines like interleukin 6 (IL-6), TNF-a, and chemokines [10,11]. Unlike allergens, LPS induces no degranulation of MC, but like allergens, it stimulates the de novo synthesis and release of cytokines in these cells [9].Activation of cells by LPS is mediated by the Toll-like receptor 4 (TLR4), a member of the highly conserved protein family of TLR, which are specialized in the recognition of microbial components. In mice, defects in TLR4 result in LPS unresponsiveness [12]. For functional interaction with LP...

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Elevated levels of soluble CD14 in serum of patients with acute Plasmodium falciparum malaria

Cited by 32 publications

References 37 publications

A Common Single Nucleotide Polymorphism in the CD14 Promoter Decreases the Affinity of Sp Protein Binding and Enhances Transcriptional Activity

A Common Single Nucleotide Polymorphism in the CD14 Promoter Decreases the Affinity of Sp Protein Binding and Enhances Transcriptional Activity

Low levels of mammalian TGF-β1 are protective against malaria parasite infection, a paradox clarified in the mosquito host

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

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