Crucial implication of protein kinase C (PKC)-delta, PKC-zeta, ERK-1/2, and p38 MAPK in migration of human asthmatic eosinophils.
Asthma is associated with an eosinophil infiltration into the bronchial mucosa. 5-Oxo-6,8,11,14(E,Z,Z,Z)-eicosatetraenoic acid (5-oxo-ETE), a potent eosinophil chemotactic factor, activates cell motility, adherence, and proteolysis, notably, by promoting CD11b expression, matrix metalloproteinase (MMP)-9 secretion, and plasmin generation. We investigated the intracellular signaling pathways implicated in these various steps by using different, selective inhibitors. Human eosinophil migration through a reconstituted basement membrane in response to 5-oxo-ETE was greatly inhibited (>or=72%) by the protein kinase C (PKC)-delta, PKC-zeta, ERK-1/2, and p38 inhibitors. Our findings indicate that PKC-delta mediates cell motility, CD11b expression, and MMP-9 granule release. PKC-zeta is also largely involved in eosinophil migration, although its specific targets remain undefined. ERK-1/2 and p38 modulate CD11b expression; ERK-1/2 is also involved in long-term MMP-9 secretion and p38 in the plasmin activation system. We demonstrated the crucial implication of PKC-delta, PKC-zeta, ERK-1/2, and p38 in human blood eosinophil migration through extracellular matrix components. Targeting specific pathways may have therapeutic potential for the treatment of allergic airway inflammation.
Langlois
Anick
A
Unité de Recherche en Pneumologie, Centre de Recherche de l'Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Québec City, Quebec, Canada.
Chouinard
Francois
F
Flamand
Nicolas
N
Ferland
Claudine
C
Rola-Pleszczynski
Marek
M
Laviolette
Michel
M
D001095:Arachidonic Acids / Q000502:physiology; D001249:Asthma / Q000378:metabolism* / Q000473:pathology*; D039481:CD11b Antigen / Q000096:biosynthesis; D002465:Cell Movement; D004804:Eosinophils / Q000473:pathology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta
D001095:Arachidonic Acids; D039481:CD11b Antigen; D020780:Matrix Metalloproteinase 9; D048052:Mitogen-Activated Protein Kinase 3; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099221:Protein Kinase C zeta; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid