Compartmentalization of PDE-4 and cAMP-dependent protein kinase in neutrophils and macrophages during phagocytosis |
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Authors: | Katherine B Pryzwansky Sudha Kidao Elizabeth P Merricks |
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Institution: | (1) Department of Pathology, University of North Carolina, 27599-7525 Chapel Hill, NC |
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Abstract: | The compartmentalization of cAMP in human neutrophils during phagocytosis of serum-opsonized zymosan suggests that cAMP is
an important second messenger for regulating phagocytosis. Type 4 cAMP-specific phosphodiesterase (PDE-4), cAMP-dependent
protein kinase (PKA), and adenylate cyclase are the principal effector molecules for cAMP regulation in phagocytes. Immunofluorescence
microscopy demonstrated that PDE-4 isoforms (HSPDE-4A, HSPDE-4B, HSPDE-4D) were targeted to the forming phagosome in neutrophils,
and were colocalized with the catalytic subunit of PKA and degranulated myeloperoxidase. Phagocytosis and accumulation of
PDE-4 and PKA near adherent zymosan were inhibited by elevating cAMP levels with forskolin or rolipram. cAMP, PDE-4, and PKA
were localized at sites of zymosan adherence in cells treated with cytochalasin D to inhibit phagosome formation, suggesting
that zymosan engagement to Fc/CR3 receptors triggers cAMP elevations at sites of phagocytosis. HSPDE-4A, HSPDE-4B, HSPDE-4D,
and PKA also were localized at the forming phagosome in monocyte-derived macrophages, and the lysosomal marker CD63 demonstrated
the absence of PDE-4 around internalized phagolysosomes. These results suggest that cAMP levels are focally regulated by PDE-4
at the nascent phagosome, and that PKA may phosphorylate proteins associated with pseudopodia formation and phagosome internalization. |
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Keywords: | Neutrophils macrophages phagocytosis cAMP phosphodiesterase cAMP-dependent protein kinase |
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