Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils.
In allergic diseases, the cytokines interleukin (IL)5 and granulocyte/macrophage colony-stimulating factor (GM-CSF) are upregulated and have been proposed to cause blood and tissue eosinophilia by inhibition of eosinophil apoptosis. We demonstrate herein, in freshly isolated human eosinophils, that the IL-3/IL-5/GM-CSF receptor beta subunit interacts with cytoplasmic tyrosine kinases to induce phosphorylation of several cellular substrates, including the beta subunit itself. The Lyn and Syk intracellular tyrosine kinases constitutively associate at a low level with the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils. Stimulation with GM-CSF or IL-5 results in a rapid and transient increase in the amount of Lyn and Syk associated with the IL-3/IL-5/GM-CSF receptor beta subunit. Lyn is required for optimal tyrosine phosphorylation and activation of Syk. In contrast, Syk is not required for optimal tyrosine phosphorylation and activation of Lyn. These data suggest that Lyn is proximal to Syk in a tyrosine kinase cascade that transduces IL-3, IL-5, or GM-CSF signals. Compatible with this model, both Lyn and Syk are essential for the activation of the antiapoptotic pathway(s) induced through the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils.
Yousefi
S
S
Swiss Institute of Allergy and Asthma Research, University of Zurich, Switzerland.
Hoessli
D C
DC
Blaser
K
K
Mills
G B
GB
Simon
H U
HU
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D002451:Cell Compartmentation; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000302:isolation & purification; D018123:Receptors, Interleukin / Q000302:isolation & purification; D015398:Signal Transduction; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism
D004792:Enzyme Precursors; D006133:Growth Substances; D015848:Interleukin-5; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases