Serum Amyloid P Component Is the Shiga Toxin 2-neutralizing Factor in Human Blood

Kimura, T.; Tani, Shinobu; Matsumoto, Yoh-ichi; Takeda, Tae

doi:10.1074/jbc.m107819200

Cited by 51 publications

(51 citation statements)

References 34 publications

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“…SAP neutralizes Stx2, but not Stx1, in vitro, and human SAP protects mice from Stx2-induced disease (14). The Stx2-neutralizing effect is not present in the sera of nonhuman species tested so far (15), consistent with the much higher binding avidity of human SAP than mouse SAP to other known ligands (18).…”

supporting

confidence: 58%

“…On the other hand, SAP clearly contributes to host resistance against bacterial infections (17,44,45), although the mechanisms are still unknown. However, human SAP is known to bind to Stx2, neutralizing its toxic effects (14,15). We showed that SAP markedly reduced MAPK activation and apoptosis of Stx2-injured podocytes, implying that SAP may protect podocytes from severe Stx2-induced damage.…”

Section: Discussionmentioning

confidence: 75%

“…It has been suggested that neurological involvement may be due to deficiency or impaired function of an Stx2-neutralizing factor (13) in affected patients, in which case plasma supply and exchange might be beneficial. Various candidates for such a neutralizing factor have been investigated, and serum amyloid P component (SAP) appears to be the most promising (14,15). SAP is one member of the pentraxin family; the other member is C-reactive protein (CRP) (16).…”

mentioning

confidence: 99%

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Protection of Human Podocytes from Shiga Toxin 2-Induced Phosphorylation of Mitogen-Activated Protein Kinases and Apoptosis by Human Serum Amyloid P Component

et al. 2014

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jHemolytic uremic syndrome (HUS) is mainly induced by Shiga toxin 2 (Stx2)-producing Escherichia coli. Proteinuria can occur in the early phase of the disease, and its persistence determines the renal prognosis. Stx2 may injure podocytes and induce proteinuria. Human serum amyloid P component (SAP), a member of the pentraxin family, has been shown to protect against Stx2-induced lethality in mice in vivo, presumably by specific binding to the toxin. We therefore tested the hypothesis that SAP can protect against Stx2-induced injury of human podocytes. To elucidate the mechanisms underlying podocyte injury in HUS-associated proteinuria, we assessed Stx2-induced activation of mitogen-activated protein kinases (MAPKs) and apoptosis in immortalized human podocytes and evaluated the impact of SAP on Stx2-induced damage. Human podocytes express Stx2-binding globotriaosylceramide 3. Stx2 applied to cultured podocytes was internalized and then activated p38␣ MAPK and c-Jun N-terminal kinase (JNK), important signaling steps in cell differentiation and apoptosis. Stx2 also activated caspase 3, resulting in an increased level of apoptosis. Coincubation of podocytes with SAP and Stx2 mitigated the effects of Stx2 and induced upregulation of antiapoptotic Bcl2. These data suggest that podocytes are a target of Stx2 and that SAP protects podocytes against Stx2-induced injury. SAP may therefore be a useful therapeutic option.

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supporting

confidence: 58%

Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

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Protection of Human Podocytes from Shiga Toxin 2-Induced Phosphorylation of Mitogen-Activated Protein Kinases and Apoptosis by Human Serum Amyloid P Component

et al. 2014

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“…SAP Ϫ/Ϫ mice have been shown to be resistant to lethal infection by organisms to which SAP binds but to be more susceptible to those which SAP does not bind, suggesting that increased SAP might be beneficial to the host during pneumococcal infection (42). Interestingly, SAP has recently been shown to be the Escherichia coli Shiga toxin 2-neutralizing factor of human plasma (34).…”

Section: Vol 71 2003 Pneumolysin-dependent and -Independent Gene Exmentioning

confidence: 99%

Pneumolysin-Dependent and -Independent Gene Expression Identified by cDNA Microarray Analysis of THP-1 Human Mononuclear Cells Stimulated byStreptococcus pneumoniae

Rogers

Thornton²,

Barker

et al. 2003

Infect Immun

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Pneumolysin is an important virulence factor of Streptococcus pneumoniae, interacting with the membranes of host cells to elicit a multitude of inflammatory responses. We used cDNA microarrays to identify genes which are responsive to S. pneumoniae in a pneumolysin-dependent and -independent fashion. The THP-1 human monocytic cell line was coincubated for 3 h with medium alone, with the virulent type 2 S. pneumoniae strain D39, or with the isogenic strain PLN, which does not express pneumolysin. RNA was isolated from the monocytes and hybridized on cDNA microarrays. Of 4,133 genes evaluated, 142 were found to be responsive in a pneumolysin-dependent fashion, whereas 40 were found to be responsive independent of pneumolysin. Genes that were up-regulated in cells exposed to D39 relative to those exposed to PLN included genes encoding proteins such as mannose binding lectin 1, lysozyme, ␣-1 catenin, cadherin 17, caspases 4 and 6, macrophage inflammatory protein 1␤ (MIP-1␤), interleukin 8 (IL-8), monocyte chemotactic protein 3 (MCP-3), IL-2 receptor ␤ (IL-2R␤), IL-15 receptor ␣ (IL-15R␣), interferon receptor 2, and prostaglandin E synthase. Down-regulated genes included those encoding complement component receptor 2/CD21, platelet-activating factor acetylhydrolase, and oxidized low-density lipoprotein receptor 1 (OLR1). Pneumolysin-independent responses included down-regulation of the genes encoding CD68, CD53, CD24, transforming growth factor ␤2, and signal transducers and activators of transcription 1. These results demonstrate the striking effects of pneumolysin on the host cell upon exposure to S. pneumoniae.

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“…All four are secreted glycoproteins widely distributed in most physiological fluids, including plasma and CSF (Barrett 1981;Baltz et al, 1982;Bowman and Kurosky 1982;. Moreover, all bind to a broad range of ligands (Barrett 1981;Capiau et al, 1986;Katnik et al, 1987;Aruga et al, 1993;Katnik et al, 1993;Zahedi 1996;Ashton et al, 1997;Langlois et al, 1997;Zahedi 1997;Kurdowska et al, 2000;Wilson and Easterbrook-Smith 2000;Kimura et al, 2001;Sen and Heegaard 2002) and have been found associated with clinical amyloid deposits in vivo (Table (1)) (Powers et al, 1981;Baltz et al, 1982;Van Gool et al, 1993;McHattie and Edington 1999;Calero et al, 2000). In addition all have been shown to mediate receptormediated endocytosis of ligands (see below).…”

Section: Extracellular Chaperonesmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Serum Amyloid P Component Is the Shiga Toxin 2-neutralizing Factor in Human Blood

Cited by 51 publications

References 34 publications

Protection of Human Podocytes from Shiga Toxin 2-Induced Phosphorylation of Mitogen-Activated Protein Kinases and Apoptosis by Human Serum Amyloid P Component

Protection of Human Podocytes from Shiga Toxin 2-Induced Phosphorylation of Mitogen-Activated Protein Kinases and Apoptosis by Human Serum Amyloid P Component

Pneumolysin-Dependent and -Independent Gene Expression Identified by cDNA Microarray Analysis of THP-1 Human Mononuclear Cells Stimulated byStreptococcus pneumoniae

Extracellular Chaperones and Amyloids

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