Activation of the plasma kallikrein-kinin system on human lung epithelial cells.
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.
School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, 35 Stirling Highway, Perth 6009, Western Australia, Australia. julius.varano@gmail.com
Julius F Varano della
JF
Vergiliana
Nithiananthan
N
Asokananthan
Geoffrey A
GA
Stewart
D001920:Bradykinin / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016234:Kallikrein-Kinin System / Q000502:physiology*; D007704:Kininogens / Q000037:antagonists & inhibitors / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009675:Novobiocin / Q000494:pharmacology; D011288:Prekallikrein / Q000037:antagonists & inhibitors / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
C087299:C1QBP protein, human; D002352:Carrier Proteins; D018841:HSP90 Heat-Shock Proteins; D007704:Kininogens; D024101:Mitochondrial Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D009675:Novobiocin; D011288:Prekallikrein; D001920:Bradykinin