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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/L505    most recent 00347.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Coffman, L. G. Articles by Torti, S. V. Search for Related Content PubMed PubMed Citation Articles by Coffman, L. G. Articles by Torti, S. V.

Cleavage of high-molecular-weight kininogen by elastase and tryptase is inhibited by ferritin

¹Program in Molecular Medicine, Departments of ²Biochemistry, ³Pathology, and ⁴Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina; ⁵Department of Biochemistry and Molecular Biology, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee; ⁶Institute of Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany; ⁷Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill; ⁸Department of Cancer Biology and ⁹Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 23 August 2007 ; accepted in final form 10 January 2008

Ferritin is a protein principally known for its role in iron storage. We have previously shown that ferritin can bind high-molecular-weight kininogen (HK). Upon proteolytic cleavage by the protease kallikrein, HK releases the proinflammatory peptide bradykinin (BK) and other biologically active products, such as two-chain high-molecular-weight kininogen, HKa. At inflammatory sites, HK is oxidized, which renders it a poor substrate for kallikrein. However, oxidized HK remains a good substrate for elastase and tryptase, thereby providing an alternative cleavage mechanism for HK during inflammation. Here we report that ferritin can retard the cleavage of both native HK and oxidized HK by elastase and tryptase. Initial rates of cleavage were reduced 45–75% in the presence of ferritin. Ferritin is not a substrate for elastase or tryptase and does not interfere with the ability of either protease to digest a synthetic substrate, suggesting that ferritin may impede HK cleavage through direct interaction with HK. Immunoprecipitation and solid phase binding studies reveal that ferritin and HK bind directly with a K_d of 134 nM. To test whether ferritin regulates HK cleavage in vivo, we used THP-1 cells, a human monocyte/macrophage cell line that has been used to model pulmonary inflammatory cells. We observed that ferritin impedes the cleavage of HK by secretory proteases in stimulated macrophages. Furthermore, ferritin, HK, and elastase are all present in or on alveolar macrophages in a mouse model of pulmonary inflammation. Collectively, these results implicate ferritin in the modulation of HK cleavage at sites of inflammation.

inflammation; bradykinin

This article has been cited by other articles:

				L. G. Coffman, D. Parsonage, R. D'Agostino Jr., F. M. Torti, and S. V. Torti Regulatory effects of ferritin on angiogenesis PNAS, January 13, 2009; 106(2): 570 - 575. [Abstract] [Full Text] [PDF]