Stimulated human neutrophils form biologically active kinin peptides from high and low molecular weight kininogens

Stuardo, Miguel; González, Carlos B.; Nualart, Francisco; Borić, Mauricio P.; Corthorn, Jenny; Bhoola, K. D.; Figueroa, Carlos D.

doi:10.1189/jlb.1103546

Cited by 42 publications

(34 citation statements)

References 32 publications

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“…As proposed for endothelial cells (Schmaier, 2007), initial activation of the plasma KKS on the respiratory epithelium might occur independent of FXIIa, but FXII autoactivation (Reddigari et al, 1993b) or conversion by PK would augment this process by activating PPK directly. Although our data demonstrate activation of the plasma KKS by respiratory epithelial cells per se, host-derived (Imamura et al, 1996;Kozik et al, 1998;Stuardo et al, 2004) or microbial (Molla et al, 1989;Imamura et al, 1994) proteases present at inflammatory foci might also activate HK or PPK bound to the epithelium.…”

Section: Discussioncontrasting

confidence: 48%

Activation of the plasma kallikrein-kinin system on human lung epithelial cells

Vergiliana

Asokananthan

Stewart³

2010

Biological Chemistry

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Activation of the tissue kallikrein-kinin system (KKS) plays a major inflammatory role in the lung, but the contribution of the plasma KKS remains unclear. Plasma KKS involves assembly and activation of high molecular weight kininogen (HK) and plasma prekallikrein (PPK) on cell surfaces, resulting in the liberation of the inflammatory peptide, bradykinin (BK), from HK by plasma kallikrein (PK). To this end, we determined the possible contribution of plasma KKS in BK formation using airway epithelium. The HK binding proteins, urokinase plasminogen activator receptor, cytokeratin 1 and gC1qR, were expressed on transformed A549 and BEAS-2B cell lines, as well as on normal lung tissue, but Mac-1 was absent. A549 cells bound FITC-labelled HK, which was only partially inhibited by a combination of antibodies to the HK binding proteins. HK-PPK complex activation on the transformed epithelial cell lines, as well as primary epithelial cells, resulted in PK formation and liberation of BK. HK-PPK activation was inhibited by cysteine, BK and protamine, and by novobiocin, a heat shock protein 90 (HSP90) inhibitor. In summary, lung epithelial cells support the assembly and activation of the plasma KKS by a mechanism dependent on HSP90, and could contribute to KKS-mediated inflammation in lung disease.

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Section: Discussioncontrasting

confidence: 48%

Activation of the plasma kallikrein-kinin system on human lung epithelial cells

Vergiliana

Asokananthan

Stewart³

2010

Biological Chemistry

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“…retention times to bradykinin and Met-Lys-bradykinin. The biological activity was mediated by kinin B 2 receptors (36). We have taken these results further and demonstrated, using Triton X-100 lyzed neutrophils, that PR3, in a dose-dependent, specific, and physiological manner, is almost exclusively responsible for HK proteolysis and that the product of this reaction is a novel kinin peptide that we have termed PR3-kinin.…”

Section: Discussionmentioning

confidence: 86%

“…Neutrophil-derived tissue kallikrein participated in kinin release as the reaction was blocked by antihuman urinary kallikrein but not by antineutrophil elastase Ab (36). The generated kinins were analyzed by HPLC and radioimmunoassay and shown to have similar FIGURE 5.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-Derived Proteinase 3 Induces Kallikrein-Independent Release of a Novel Vasoactive Kinin

Kahn¹,

Hellmark²,

Leeb-Lundberg

et al. 2009

The Journal of Immunology

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The kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH2-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and α1-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B1 receptors, but did not bind to B2 receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B2 receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B1 and B2 receptors as demonstrated using wild-type and B1 overexpressing rats as well as wild-type and B2 receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.

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“…The presence of tissue kallikrein in human neutrophils was first reported in 1989 [18], and subsequent studies showed that high and low molecular weight kininogens are present on the neutrophil cell membrane [19]. Neutrophils therefore have the capacity for localized formation of biologically active kinin peptides that could produce autocrine and paracrine effects by binding to their respective receptors [20,21]. However until recently, evidence that kinin receptors are present on human neutrophils was restricted to a radioligand binding study demonstrating binding sites for kinin B 1 and B 2 agonists in purified plasma membrane preparations [22].…”

Section: Discussionmentioning

confidence: 99%