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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

High-Molecular-Weight Kininogen Fragments Stimulate the Secretion of Cytokines and Chemokines Through uPAR, Mac-1, and gC1qR in Monocytes.

OBJECTIVE: Plasma high-molecular-weight kininogen (HK) is cleaved in inflammatory diseases by kallikrein to HKa with release of bradykinin (BK). We postulated a direct link between HKa and cytokine/chemokine release. METHODS AND RESULTS: HKa, but not BK, releases cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and chemokines IL-8 and MCP-1 from isolated human mononuclear cells. At a concentration of 600 nM, glutathione-S-transferase (GST) fusion proteins of kininogen domain 3 (D3), a fragment of domain 3, E7P (aaG255-Q292), HK domain 5 (D5), the D5 recombinant peptides HG (aa K420-D474) and HGK (aa H475-S626) stimulated secretion of IL-1beta from mononuclear cells. Monoclonal antibodies (MAbs) specific for D5 or specific for D3 blocked release of IL-1beta by HKa, supporting the importance of both domains. Antibodies to HK receptors on leukocytes including Mac-1, LFA-1, uPAR, and C1qR inhibited IL-1beta secretion induced by tKa 98%, 89%, 85%, and 62%, respectively. Fractionation of mononuclear cells identified the responsible cell, a blood monocyte. Inhibitors of signaling pathways NFkB, JNK, and p38 but not extracellular signal-regulated kinase ( ERK) decreased cytokine release from mononuclear cells. HKa increased the synthesis of IL-1beta as deduced by an increase of IL-1beta mRNA at 1 to 2 hours. CONCLUSIONS: HKa domains 3 and 5 may contribute to the pathogenesis of inflammatory diseases by releasing IL-1beta from human monocytes using intracellular signaling pathways initiated by uPAR, beta2 integrins and gC1qR.[1]

References

  1. High-Molecular-Weight Kininogen Fragments Stimulate the Secretion of Cytokines and Chemokines Through uPAR, Mac-1, and gC1qR in Monocytes. Khan, M.M., Bradford, H.N., Isordia-Salas, I., Liu, Y., Wu, Y., Espinola, R.G., Ghebrehiwet, B., Colman, R.W. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
 
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