Actin cytoskeleton-dependent down-regulation of early IgE-mediated signaling in human basophils.
Two regions of down-regulation of FcepsilonRI [high-affinity immunogloublin E (IgE) receptor] signaling have been localized recently in basophils. An early down-regulatory step is located proximal to syk and appears responsible for a transient syk phosphorylation in antigen-stimulated basophils. A second, more distal region appears responsible for the transient activation of the ras-extracellular-regulated kinase (Erk) pathway when syk phosphorylation is sustained in anti-IgE-stimulated basophils. As the actin cytoskeleton has been demonstrated to inhibit the early FcepsilonRI signaling in rat basophilic leukemia cells, we explored the hypothesis that the actin cytoskeleton was responsible for the transience of syk phosphorylation in antigen-stimulated basophils. The inhibition of F-actin polymerization with latrunculin A induced a sustained syk phosphorylation in basophils stimulated with an optimal dose of the antigen benzyl penicilloyl-human serum albumin. However, in the presence of latrunculin A, Erk phosphorylation remained transient after stimulation with the antigen or anti-IgE. Latrunculin A also increased downstream events such as histamine release, leukotriene C(4) release, and the intracellular calcium signal, although some of these effects were not specific for an immunologic stimulus. Our results suggest that the actin cytoskeleton is responsible for down-regulation of FcepsilonRI signaling at a point located proximal to syk phosphorylation. Moreover, the fact that latrunculin A did not result in sustained Erk phosphorylation supports the presence of a second down-regulatory step between syk and Erk that cannot be overcome by a sustained early signal.
Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA.
Natalia
N
Vilariño
Donald W
DW
MacGlashan
D000199:Actins / Q000502:physiology*; D001491:Basophils / Q000378:metabolism* / Q000648:ultrastructure; D003599:Cytoskeleton / Q000502:physiology*; D015536:Down-Regulation; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D018631:ras Proteins / Q000378:metabolism
D000199:Actins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606898:Syk protein, rat; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins