Pathways for eosinophil lipid body induction: differing signal transduction in cells from normal and hypereosinophilic subjects.
Although lipid bodies, inducible cytoplasmic inclusions active in arachidonic acid metabolism, are abundant in activated leukocytes, including eosinophils, mechanisms for eosinophil lipid body formation are not certain. Eosinophils from hypereosinophilic syndrome (HES) donors contained about twice (approximately 18/cell) as many lipid bodies as eosinophils froin normal donors (approximately 10/cell). By immunocytochemistry both 5- and 15-lipoxygenases were localized at lipid bodies in HES eosinophils. Platelet-activating factor (PAF) induced rapid, receptor-mediated increases in lipid bodies in normal and HES eosinophils. Protein kinase C (PKC) inhibitors, chelerythrine and calphostin C, inhibited PAF-induced lipid body formation partially in normal and HES eosinophils. In HES, but not normal, eosinophils, PAF-induced lipid body formation was completely blocked by two tyrosine kinase inhibitors, herbimycin A and genistein, which were not acting on 5-lipoxygenase because they also blocked 5-HETE-induced lipid body formation in HES, and not normal, eosinophils. After 24 h culture with eosinophil growth factor cytokines [interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM-CSF alone but not IL-5 or IL-3 alone], normal eosinophils were induced to exhibit an HES-like phenotype, including increased lipid body numbers and tyrosine kinase-dependent signaling for PAF-induced lipid body formation. Thus, signal transduction mechanisms involved in PAF-induced lipid body formation in eosinophils can be differentially recruited. Tyrosine kinase-dependent signaling is not involved in normal eosinophils, but is active in HES eosinophils and in normal eosinophils cultured with GM-CSF. PKC- and tyrosine kinase-dependent pathways are involved in the formation of eosinophil lipid bodies, which may facilitate enhanced synthesis of lipoxygenase-derived eicosanoids.
Charles A. Dana Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
P T
PT
Bozza
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W
Yu
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J
Cassara
P F
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Weller
D000328:Adult; D001093:Arachidonate 15-Lipoxygenase / Q000097:blood; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D016227:Benzoquinones; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004802:Eosinophilia / Q000097:blood*; D004804:Eosinophils / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D019833:Genistein / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D002479:Inclusion Bodies / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure*; D007377:Interleukin-3 / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008055:Lipids / Q000097:blood; D010750:Phosphoproteins / Q000097:blood; D019000:Phosphotyrosine; D010972:Platelet Activating Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000097:blood; D011809:Quinones / Q000494:pharmacology; D012016:Reference Values; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000502:physiology*
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D015848:Interleukin-5; D047029:Lactams, Macrocyclic; D008055:Lipids; D010750:Phosphoproteins; D010972:Platelet Activating Factor; D011809:Quinones; D017828:Rifabutin; D019000:Phosphotyrosine; C020754:herbimycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019833:Genistein; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase; D011505:Protein-Tyrosine Kinases