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Signal regulatory proteins negatively regulate immunoreceptor-dependent cell activation.
H Liénard1, P Bruhns, O Malbec
1Laboratoire d'Immunologie Cellulaire et Clinique, INSERM U.255, Institut Curie, 75005 Paris, France.
The Journal of Biological Chemistry
|November 5, 1999
Summary
Signal regulatory proteins (SIRPalpha) inhibit cell proliferation and activation. This study shows SIRPalpha negatively regulates mast cell activation via ITAM-dependent pathways, impacting mediator secretion and cytokine synthesis.
Area of Science:
- Immunology
- Cell Biology
- Molecular Signaling
Background:
- Signal regulatory proteins of the alpha subtype (SIRPalpha) are immunoglobulin superfamily molecules known to negatively regulate protein tyrosine kinase receptor-dependent cell proliferation.
- SIRPalpha possesses intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs) that recruit protein tyrosine phosphatases (SHPs) upon tyrosyl phosphorylation.
- ITIM-bearing molecules typically inhibit cell activation mediated by immunoreceptor tyrosine-based activation motifs (ITAMs).
Purpose of the Study:
- To investigate whether SIRPalpha can negatively regulate ITAM-dependent cell activation in hematopoietic cells, specifically mast cells.
- To determine the mechanism by which SIRPalpha influences IgE-induced mast cell activation.
Main Methods:
- Detection of SIRPalpha transcripts in human mast cells.
- Utilizing a chimeric molecule comprising SIRPalpha's transmembrane and intracytoplasmic domains.
- Coaggregation of the SIRPalpha chimera with high-affinity IgE receptors (FcepsilonRI) on mast cells.
- Assessing IgE-induced mediator secretion, cytokine synthesis, tyrosyl phosphorylation, SHP recruitment, Ca(2+) mobilization, and Erk1/Erk2 activation.
Main Results:
- SIRPalpha transcripts were identified in human mast cells.
- A SIRPalpha chimera inhibited IgE-induced mediator secretion and cytokine synthesis when coaggregated with FcepsilonRI.
- This inhibition correlated with SIRPalpha tyrosyl phosphorylation, SHP-1 and SHP-2 recruitment, decreased FcepsilonRI ITAM phosphorylation, reduced Ca(2+) mobilization, and abolished Erk1/Erk2 activation.
Conclusions:
- SIRPalpha negatively regulates ITAM-dependent mast cell activation, extending its known inhibitory role beyond receptor tyrosine kinase-dependent proliferation.
- SIRPalpha acts as an inhibitory signal in mast cells by modulating FcepsilonRI signaling pathways.
- The findings elucidate a novel mechanism of immune cell regulation involving SIRPalpha and ITAM-bearing receptors.