title: The serine protease plasmin triggers expression of the CC-chemokine ligand 20 in dendritic cells via Akt/NF-κB-dependent pathways.
abstract: The number of dendritic cells is increased in advanced atherosclerotic lesions. In addition, plasmin, which might stimulate dendritic cells, is generated in atherosclerotic lesions. Here, we investigated cytokine and chemokine induction by plasmin in human dendritic cells. In human atherosclerotic vessel sections, plasmin colocalized with dendritic cells and the CC-chemokine ligand 20 (CCL20, MIP-3α), which is important for homing of lymphocytes and dendritic cells to sites of inflammation. Stimulation of human dendritic cells with plasmin, but not with catalytically inactivated plasmin, induced transcriptional regulation of CCL20. By contrast, proinflammatory cytokines such as TNF-α, IL-1α, and IL-1β were not induced. The plasmin-mediated CCL20 expression was preceded by activation of Akt and MAP kinases followed by activation of the transcription factor NF-κB as shown by phosphorylation of its inhibitor IκBα, by nuclear localization of p65, its phosphorylation, and binding to NF-κB consensus sequences. The plasmin-induced CCL20 expression was dependent on Akt- and ERK1/2-mediated phosphorylation of IκBα on Ser32/36 and of p65 on Ser276, whereas p38 MAPK appeared to be dispensable. Thus, plasmin triggers release of the chemokine CCL20 from dendritic cells, which might facilitate accumulation of CCR6(+) immune cells in areas of plasmin generation such as inflamed tissues including atherosclerotic lesions.
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Universitat Ulm, Ulm, Germany.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Li
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
mesh_terms: D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005341:Fibrinolysin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D016328:NF-kappa B; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005341:Fibrinolysin