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Sökning: WFRF:(Müller Esterl Werner)

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1.
  • Kenne, Ellinor, et al. (författare)
  • Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation
  • Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : The Federation of American Societies for Experimental Biology. - 1530-6860. ; 33:2, s. 2599-2609
  • Tidskriftsartikel (refereegranskat)abstract
    • Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.
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2.
  • Ben Nasr, Abdelhakim, et al. (författare)
  • Absorption of kininogen from human plasma by Streptococcus pyogenes is followed by the release of bradykinin
  • Ingår i: Biochemical Journal. - : Portland Press. - 0264-6021. ; 326:3, s. 657-660
  • Tidskriftsartikel (refereegranskat)abstract
    • H-kininogen (high-molecular-mass kininogen, HK) is the precursor of the vasoactive peptide hormone bradykinin (BK). Previous work has demonstrated that HK binds to Streptococcus pyogenes through M-proteins, fibrous surface proteins and important virulence factors of these bacteria. Here we find that M-protein-expressing bacteria absorb HK from human plasma. The HK bound to the bacteria was found to be cleaved, and analysis of the degradation pattern suggested that the cleavage of HK at the bacterial surface is associated with the release of BK. Moreover, addition of activated plasma prekallikrein to bacteria preincubated with human plasma, resulted in BK release. This mechanism, by which a potent vasoactive and proinflammatory peptide is generated at the site of infection, should influence the host-parasite relationship during S. pyogenes infections.
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3.
  • Ben Nasr, Abdelhakim, et al. (författare)
  • Assembly of human contact phase factors and release of bradykinin at the surface of curli-expressing Escherichia coli
  • 1996
  • Ingår i: Molecular Microbiology. - : Wiley-Blackwell. - 1365-2958. ; 20:5, s. 35-927
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous work has demonstrated that most strains of the human pathogen Streptococcus pyogenes bind kininogens through M protein, a fibrous surface protein and virulence determinant. Here we find that strains of several other pathogenic bacterial species, both Gram-positive and Gram-negative, isolated from patients with sepsis, also bind kininogens, especially kininogen (HK). The most pronounced interaction was seen between HK and Escherichia coli. Among clinical isolates of E. coli, the majority of the enterohaemorrhagic, enterotoxigenic, and sepsis strains, but none of the enteroinvasive and enteropathogenic strains, bound HK. Binding of HK to E. coli correlated with the expression of curli, another fibrous bacterial surface protein, and the binding of HK to purified curli was specific, saturable, and of high affinity; Ka = 9 x 10(7) M-1. Other contact phase proteins such as factor XI, factor XII, and prekallikrein bound to curliated E. coli, but not to an isogenic curli-deficient mutant strain, suggesting that contact phase activation may occur at the surface of curliated bacteria. Kininogens are also precursor molecules of the vasoactive kinins. When incubated with human plasma, curli-expressing bacteria absorbed HK. Addition of purified plasma kallikrein to the HK-loaded bacteria resulted in a rapid and efficient release of bradykinin from surface-bound HK. The assembly of contact phase factors at the surface of pathogenic bacteria and the release of the potent proinflammatory and vasoactive peptide bradykinin, should have a major impact on the host-microbe relationship and may contribute to bacterial pathogenicity and virulence.
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4.
  • Ben Nasr, Abdelhakim, et al. (författare)
  • Human kininogens interact with M protein, a bacterial surface protein and virulence determinant.
  • 1995
  • Ingår i: Biochemical Journal. - : Portland Press Limited. - 0264-6021. ; 305:1, s. 80-173
  • Tidskriftsartikel (refereegranskat)abstract
    • Streptococcus pyogenes, the most significant streptococcal species in clinical medicine, expresses surface proteins with affinity for several human plasma proteins. Here we report that kininogens, the precursors to the vasoactive kinins, bind to the surface of S. pyogenes. M protein, a surface molecule and a major virulence factor-in these bacteria, occurs in > 80 different serotypes. Among 49 strains of S. pyogenes, all of different M serotypes, 41 bound radiolabelled kininogens, whereas 6 M protein-negative mutant strains showed no affinity. M protein of most serotypes bind fibrinogen, and among the 55 strains tested, binding of kininogens was closely correlated to fibrinogen binding (r = 0.88, P < 0.0001). Western blotting, slot binding and enzyme immunoassay experiments demonstrated that M proteins isolated from S. pyogenes of three different M protein serotypes (M1, M6 and M46) bound kininogens. The affinity between kininogens and M1 protein was determined to be 5 x 10(7) M-1 and < or = 10(6) M-1 for high molecular weight (H-kininogen) and low molecular weight kininogen, respectively. The kininogen binding site was tentatively mapped to the N-terminal portion of M1 protein, and this site does not overlap the specific and separate binding sites for albumin, IgG and fibrinogen using monoclonal antibodies to, and synthetic peptides of, the kininogen sequence, the major M protein-binding site(s) was mapped to the C-terminal portion of the H-kininogen light chain. We anticipate that the kininogen-M protein interaction contributes to the host-parasite relationship in S. pyogenes infections.
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5.
  • Blaukat, Andree, et al. (författare)
  • Determination of bradykinin B2 receptor in vivo phosphorylation sites and their role in receptor function
  • 2001
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 276:44, s. 40431-40440
  • Tidskriftsartikel (refereegranskat)abstract
    • Reversible phosphorylation plays important roles in G protein-coupled receptor signaling, desensitization, and endocytosis, yet the precise location and role of in vivo phosphorylation sites is unknown for most receptors. Using metabolic 32P labeling and phosphopeptide sequencing we provide a complete phosphorylation map of the human bradykinin B2 receptor in its native cellular environment. We identified three serine residues, Ser(339), Ser(346), and Ser(348), at the C-terminal tail as principal phosphorylation sites. Constitutive phosphorylation occurs at Ser(348), while ligand-induced phosphorylation is found at Ser(339) and Ser(346)/Ser(348) that could be executed by several G protein-coupled receptor kinases. In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. This was further supported by the specifically reduced Ser(346)/Ser(348) phosphorylation observed upon stimulation with a nondesensitizing B2 receptor agonist. The differential usage of clustered phosphoacceptor sites points to distinct roles of multiple kinases in controlling G protein-coupled receptor function.
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6.
  • Blaukat, Andree, et al. (författare)
  • Downregulation of bradykinin B2 receptor in human fibroblasts during prolonged agonist exposure
  • 2003
  • Ingår i: American Journal of Physiology. Heart and Circulatory Physiology. - 0363-6135 .- 1522-1539. ; 284:6, s. H1909-1916
  • Tidskriftsartikel (refereegranskat)abstract
    • Sustained activation of G protein-coupled receptors results in an attenuation of cellular responses, a phenomenon termed desensitization. Whereas mechanisms for rapid desensitization of ligand-receptor-G protein-effector systems are relatively well characterized, much less is known about long-term adaptation processes that occur in the continuous presence of an agonist. Here we have studied the fate of endogenously expressed bradykinin B(2) receptors on human fibroblasts during prolonged agonist treatment. Stimulation with bradykinin for up to 24 h resulted in a 50% reduction of surface binding sites that was paralleled by a similar decrease of total B(2) receptor protein followed by Western blotting using monoclonal antibodies to the B(2) receptor. Whereas B(2) receptor mRNA levels did not change during 24 h of agonist treatment, B(2) receptor de novo synthesis was attenuated by 35-50%, indicating translational control of B(2) receptor levels. Furthermore, the half-life of B(2) receptor protein was shortened by 20-40% as shown by (35)S-labeled pulse-chase and immunoprecipitation experiments. This study demonstrates that bradykinin B(2) receptor expression during long-term agonist treatment is primarily regulated on the (post)translational level, i.e., by attenuation of de novo synthesis and by reduction of receptor stability.
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7.
  • Herwald, Heiko, et al. (författare)
  • Activation of the contact-phase system on bacterial surfaces - A clue to serious comlications in infections deseases
  • Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956. ; 4:3, s. 298-302
  • Tidskriftsartikel (refereegranskat)abstract
    • Fever, hypotension and bleeding disorders are common symptoms of sepsis and septic shock. The activation of the contact-phase system is thought to contribute to the development of these severe disease states by triggering proinflammatory and procoagulatory cascades; however, the underlying molecular mechanisms are obscure. Here we report that the components of the contact-phase system are assembled on the surface of Escherichia coil and Salmonella through their specific interactions with fibrous bacterial surface proteins, curli and fimbriae. As a consequence, the proinflammatory pathway is activated through the release of bradykinin, a potent inducer of fever, pain and hypotension. Absorption of contact-phase proteins and fibrinogen by bacterial surface proteins depletes relevant coagulation factors and causes a hypocoagulatory state. Thus, the complex interplay of microbe surface proteins and host contact-phase factors may contribute to the symptoms of sepsis and septic shock.
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8.
  • Herwald, Heiko, et al. (författare)
  • Isolation and characterization of the kininogen-binding protein p33 from endothelial cells : Identity with the gClq receptor
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 0021-9258. ; 271:22, s. 13040-13047
  • Tidskriftsartikel (refereegranskat)abstract
    • Kininogens, the precursor proteins of the vasoactive kinins, bind specifically, reversibly, and saturably to platelets, neutrophils, and endothelial cells. Two domains of the kininogens expose major cell binding sites: domain D3 that is shared by H- and L-kininogen and domain D5H that is exclusively present in H-kininogen. Previously we have mapped the kininogen cell binding sites to 27 residues of D3 ("LDC27") and 20 residues of D5H ("HKH20"), respectively (Herwald, H., Hasan, A. A. K., Godovac-Zimmermann, J., Schmaler, A. H., and MÜller-Esterl, W. (1995) J. Biol. Chem. 270, 14634-14642; Hasan, A. A. K., Cines, D. B., Herwald, H., Schmaler, A. H., and Müller-Esterl, W. (1995) J. Biol. Chem. 270, 19256-19261). The corresponding kininogen acceptor site(s) exposed by the cell surfaces are still poorly defined. Using a non-ionic detergent, Nonidet P-40, we have been able to solubilize kininogen binding sites from an endothelial cell line, EA.hy926, in their functionally active form. Affinity chromatography of the solubilized kininogen binding sites on HKH20, a synthetic peptide representing the D5H cell binding site, allowed us to isolate a 33-kDa protein ("p33") that binds specifically and reversibly to H-kininogen with a KD (apparent dissociation constant) of 9 ±2 nM. Preparative SDS electrophoresis followed by NH2-terminal amino acid sequence analysis identified the kininogen-binding protein p33 as the gC1q receptor ("gC1qR"), an extrinsic membrane protein that interacts with the globular domains of the complement component C1q. The purified p33 binds C1q with moderate affinity, KD = 240 ±10 nM. Recombinant expression of the corresponding cDNA in Eacherichia coli demonstrated that p33 binds H-kininogen, but not L-kininogen. Peptide HKH20 but not peptide LDC27 inhibited binding of H-kininogen to the recombinant p33 in a concentration-dependent manner, indicating that H-kininogen binds to p33 via domain D5H. Recombinant p33 efficiently inhibited the binding of H-kininogen to EA.hy926 cells. Factor XII, but not prekallikrein, competed with H-kininogen binding to p33. These findings suggest that an endothelial binding protein mediates the assembly of critical components of the kinin-generating pathway on the surface of endothelial cells, thereby linking the early events of kinin formation and complement activation.
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9.
  • Herwald, Heiko, et al. (författare)
  • Mapping of the discontinuous kininogen binding site of prekallikrein : A distal binding segment is located in the heavy chain domain A4
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 0021-9258. ; 271:22, s. 13061-13067
  • Tidskriftsartikel (refereegranskat)abstract
    • Prekallikrein, the precursor to the serine proteinase kailikrein, circulates in plasma in an equimolar complex with H-kininogen. The binding to H-kininogen is mediated by the kallikrein heavy chain consisting of four "apple" domains, A1-A4, which attaches to H-kininogen with high specificity and affinity (KD = 83 UM). At least two distinct portions of the kallikrein heavy chain form this H-kininogen binding site: a proximal segment located in the NH2-terminal fragment of the heavy chain encompassing A1, and distal segment(s) located in COOH-terminal fragment spanning domains A2-A4. The proximal binding segment has been located to amino acid positions 56-86 of A1. To precisely map the distal binding segment, we have identified monoclonal antibodies directed to the COOH-terminal fragment which interfere with the H-kininogen-prekallikrein complex formation. Monoclonal antibody 13G11 binds to recombinant apple domain A4 but not to domain A3 of the prekallikrein heavy chain. Deletion mutagenesis of domain A4 narrowed down the target epitope of 13G11 to the center portion of domain A4, positions 284-331. Direct binding studies of H-kininogen to various domain A4 constructs revealed that the distal H-kininogen binding portion is located on a segment of 48 residues, which overlaps the 13G11 epitope. Hence the tight interaction of H-kininogen and prekallikrein is mediated by at least two separate sequence segments located in domains A1 and A4, respectively, of the prekallikrein heavy chain. The isolated distal binding segment significantly prolongs the partial thromboplastin time of reconstituted Williams plasma thus stressing the critical role of the prekallikrein-H-kininogen complex formation in the initiation of the endogenous blood coagulation cascade.
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10.
  • Kahn, Robin, et al. (författare)
  • Contact-system activation in children with vasculitis.
  • 2002
  • Ingår i: The Lancet. - : Elsevier. - 1474-547X. ; 360:9332, s. 535-541
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The contact system triggers the kallikrein-kinin cascade, liberating bradykinin from high-molecular-weight kininogen. Effectors of the contact system have proinflammatory and vasoactive properties. Vasculitis is a condition characterised by inflammation around vessel walls, leading to secondary tissue damage for which the underlying molecular mechanisms are poorly understood. Our aim was to investigate contact-system activation in children with vasculitis. METHODS: We compared 17 children, aged 4-19 years, with vasculitis, engaging the skin, joints, intestines, or kidneys, with 21 controls, aged 2-18 years. We analysed proteolysis of high-molecular-weight kininogen by immunoblotting. Plasma bradykinin concentrations were quantified by ELISA. Kidney and skin biopsies were stained in situ for kinins. Concentrations of heparin binding protein (HBP) were quantified by ELISA. FINDINGS: We noted extensive proteolysis of high-molecular-weight kininogen in the plasma of 13 of 17 patients, but in only one of 21 controls (p<0.0001). Bradykinin concentrations were higher in the patients' plasma (median 320 ng/L, range <1-19680) than in plasma from controls (11 ng/L, <1-304; p=0.0004). Patients had local release of kinins at sites of inflammation in kidney and skin biopsies. HBP values were raised in patients (17.4 microg/L, 5.4-237.6) compared with controls (6 microg/L, 2.5-43.4; p=0.008). INTERPRETATION: Activation of the contact system could play a part in the pathogenesis of vasculitis, and explain the inflammation, pain, vasodilatation, and oedema seen in patients.
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