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 (≥72%) by the protein kinase C (PKC)-δ, PKC-ζ, ERK-1/2, and p38 inhibitors. Our findings indicate that PKC-δ mediates cell motility, CD11b expression, and MMP-9 granule release. PKC-ζ 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-δ, PKC-ζ, 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.
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Crucial implication of protein kinase C (PKC)-δ, PKC-ζ, ERK-1/2, and p38 MAPK in migration of human asthmatic eosinophils
Langlois, Anick; Chouinard, Francois; Flamand, Nicolas; Ferland, Claudine; Rola-Pleszczynski, Marek; Laviolette, Michel
Follow Journal of Leukocyte Biology
, Volume 85 (4): 656
Fed of American Socs for Experimental Biology – Apr 1, 2009
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