Selective inhibition of the Fc epsilon RI-induced de novo synthesis of mediators by an inhibitory receptor.
Aggregation of the type 1 Fc-epsilon receptors (Fc-epsilon-RI) on mast cells initiates a network of biochemical processes culminating in secretion of both granule-stored and de novo-synthesized inflammatory mediators. A strict control of this response is obviously a necessity; nevertheless, this regulation is hardly characterized. Here we report that a prototype inhibitory receptor, the mast cell function-associated antigen (MAFA), selectively regulates the Fc-epsilon-RI stimulus-response coupling network and the subsequent de novo production and secretion of inflammatory mediators. Specifically, MAFA suppresses the PLC-gamma2-[Ca2+]i, Raf-1-Erk1/2, and PKC-p38 coupling pathways, while the Fyn-Gab2-mediated activation of PKB and Jnk is essentially unaffected. Hence, the activities of several transcription/nuclear factors for inflammatory mediators (NF-kappaB, NFAT) are markedly reduced, while those of others (Jun, Fos, Fra, p90rsk) are unaltered. This results in a selective inhibition of gene transcription of cytokines including IL-1beta, IL-4, IL-8, and IL-10, while that of TNF-alpha, MCP-1, IL-3, IL-5, or IL-13 remains unaffected. Taken together, these results illustrate the capacity of an immunoreceptor tyrosine-based inhibitory motif-containing receptor to cause tight and specific control of the production and secretion of inflammatory mediators by mast cells.
Abramson
Jakub
J
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Licht
Arieh
A
Pecht
Israel
I
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D015151:Immunoblotting; D047468:Immunoprecipitation; D018836:Inflammation Mediators / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D008156:Luciferases; D008407:Mast Cells / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D016207:Cytokines; D018836:Inflammation Mediators; C094696:Klrg1 protein, rat; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D017455:Receptors, IgE; D008156:Luciferases