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* Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan;
Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;
Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; and
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
Allergenic serine proteases are important in the pathogenesis of asthma. One of these, Pen c 13, is the immunodominant allergen produced by Penicillium citrinum. Many serine proteases induce cytokine expression, but whether Pen c 13 does so in human respiratory epithelial cells is not known. In this study, we investigated whether Pen c 13 caused IL-8 release and activated protease-activated receptors (PARs) in airway epithelial cells. In airway-derived A549 cells and normal human airway epithelial cells, Pen c 13 induced IL-8 release in a dose-dependent manner. Pen c 13 also increased IL-8 release in a time-dependent manner in A549 cells. Pen c 13 cleaved PAR-1 and PAR-2 at their activation sites. Treatment with Pen c 13 induced intracellular Ca2+ mobilization and desensitized the cells to the action of other proteases and PAR-1 and PAR-2 agonists. Moreover, Pen c 13-mediated IL-8 release was significantly decreased in Ca2+-free medium and was abolished by the protease inhibitors, PMSF and 4-(2-aminoethyl) benzenesulfonyl fluoride. Blocking Abs against the cleavage sites of PAR-1 and PAR-2, but not of PAR-4, inhibited Pen c 13-induced IL-8 production, as did inhibition of phospholipase C. Pen c 13 induced IL-8 expression via activation of ERK 1/2, and not of p38 and JNK. In addition, treatment of A549 cells or normal human airway epithelial cells with Pen c 13 increased phosphorylation of ERK 1/2 by a Ca2+-dependent pathway. These finding show that Pen c 13 induces IL-8 release in airway epithelial cells and that this is dependent on PAR-1 and PAR-2 activation and intracellular calcium.
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1 This work was supported in part by the Program for Excellence Research Teams from the Ministry of Education and Grant NSC 95-2320-B-002-109-MY3 from the National Science Council of the Republic of China.
2 Address correspondence and reprint requests to Dr. Lu-Ping Chow, Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan 100. E-mail address: lupin{at}ha.mc.ntu.edu.tw
3 Abbreviations used in this paper: PAR, protease-activated receptor; HAEC, human airway epithelial cell; AEBSF, 4-(2-aminoethyl) benzenesulfonyl fluoride; CDS, cell dissociation solution; MS, mass spectrometry; NHAEC, normal HAEC; RP, reverse peptide.
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