title: Plasmin triggers chemotaxis of monocyte-derived dendritic cells through an Akt2-dependent pathway and promotes a T-helper type-1 response.
abstract: OBJECTIVE
  Dendritic cells (DC) accumulate in atherosclerotic arteries where they can modulate atherogenesis. We investigated whether plasmin might alter the function of human DC.
  
  
  RESULTS
  Stimulation of monocyte-derived DC with plasmin elicited a time-dependent actin polymerization and chemotaxis comparable to that triggered by the standard chemoattractant formyl-methionyl-leucyl-phenylalanine. Plasmin triggered rapid activation of Akt and mitogen-activated protein kinases, followed by phosphorylation of the regulatory myosin light chain and chemotaxis. For the chemotactic DC migration, the activation of Akt and p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases were indispensable, as shown by pharmacological inhibitors. DC express Akt1 and Akt2, but not Akt3. However, in DC, plasmin activates exclusively Akt2 via a p38 mitogen-activated protein kinase-dependent pathway. Accordingly, knockdown of Akt2 with short-hairpin RNA, but not of Akt1, blocked the plasmin-induced extracellular signal-regulated kinase 1/2 activation and the chemotactic response. Moreover, plasmin-stimulated DC induced polarization of CD4(+) T cells toward the interferon-gamma-producing, proinflammatory Th1 phenotype. Consistent with a role for DC and adaptive immune response in atherogenesis, we demonstrate DC in human atherosclerotic vessels and show that plasmin is abundant in human atherosclerotic lesions, where it colocalizes with DC.
  
  
  CONCLUSIONS
  Plasmin generation in the atherosclerotic vessel wall might contribute to accumulation of DC, activation of the adaptive immune response, and aggravation of atherosclerosis.
authors.affiliation: Ulm University, Institute of Pharmacology of Natural Products & Clinical Pharmacology, Helmholtzstr. 20, D-89081 Ulm, Germany.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Li
authors.forename: Tatiana
authors.initials: T
authors.lastname: Syrovets
authors.forename: Felicitas
authors.initials: F
authors.lastname: Genze
authors.forename: Kai
authors.initials: K
authors.lastname: Pitterle
authors.forename: Alexander
authors.initials: A
authors.lastname: Oberhuber
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Orend
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmet
mesh_terms: D017306:Annexin A2 / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D005341:Fibrinolysin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000473:pathology
chemical_list: D017306:Annexin A2; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D005341:Fibrinolysin