Inhibition of protein kinases A and C demonstrates dual modes of response in human eosinophils stimulated with platelet-activating factor.
BACKGROUND
Platelet-activating factor (PAF) is a potent stimulator of human eosinophils involved in the pathogenesis of allergic diseases. However, intracellular signaling mechanisms in eosinophils involving the PAF receptor are incompletely understood.


OBJECTIVE
We sought to determine the roles of protein kinase C (PKC) and cyclic AMP-dependent protein kinase (protein kinase A [PKA]) in signaling pathways of human eosinophils stimulated with PAF.


METHODS
After pretreatment with a PKC inhibitor, bisindolylmaleimide I, or a PKA inhibitor, H89, we investigated PAF-evoked functions, such as CD11b expression, cellular adhesion, superoxide anion generation, and degranulation in human eosinophils.


RESULTS
Preincubation of eosinophils with bisindolylmaleimide I resulted in enhancement of upregulated CD11b expression and adhesion induced by PAF. H89 pretreatment also enhanced PAF-induced cellular adhesion. Superoxide anion generation and degranulation were suppressed by means of inhibition of either PKC or PKA.


CONCLUSIONS
PKC and PKA negatively regulate PAF-induced CD11b upregulation and cellular adhesion but promote eosinophil effector functions, such as superoxide anion generation and degranulation. PKC and PKA modulate PAF-evoked intracellular signaling of the eosinophil function in distinct ways.
Takizawa
Takumi
T
Department of Pediatrics, Gunma University School of Medicine, 3-39-22 Showa-machi Maebashi, Gunma 371-8511, Japan.
Kato
Masahiko
M
Kimura
Hirokazu
H
Suzuki
Masato
M
Tachibana
Atsushi
A
Obinata
Hideru
H
Izumi
Takashi
T
Tokuyama
Kenichi
K
Morikawa
Akihiro
A
D016227:Benzoquinones; D002448:Cell Adhesion / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008301:Maleimides / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D013449:Sulfonamides; D013481:Superoxides / Q000378:metabolism; D015854:Up-Regulation; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D047029:Lactams, Macrocyclic; D016177:Macrophage-1 Antigen; D008301:Maleimides; D010972:Platelet Activating Factor; D011809:Quinones; D013449:Sulfonamides; D010566:Virulence Factors, Bordetella; D013481:Superoxides; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C070515:bisindolylmaleimide I; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide