The beta subunit of the type I Fcepsilon receptor is a target for peptides inhibiting IgE-mediated secretory response of mast cells.
Peptides originally derived from complement component C3a were earlier shown to inhibit the type I FcepsilonR (FcepsilonRI)-mediated degranulation of mucosal type mast cells. In the present study, we show that C3a7, a peptide with a natural sequence, and its modified derivative, C3a9, are powerful inhibitors of the above response of both serosal and mucosal type mastocytes. We demonstrate that these peptides inhibit FcepsilonRI-induced membrane proximal events, suppress phosphorylation of the FcepsilonRI beta subunit, the protein tyrosine kinase Lyn, as well as the transient rise in free cytosolic Ca2+ level. The late phase of cellular response was also inhibited, as demonstrated by the reduced TNF-alpha secretion. Experiments using two independent methods provided evidence that the interaction site of complement-derived peptides is the FcepsilonRI beta-chain. This was further supported by fluorescence confocal microscopic colocalization and resonance energy transfer measurements. Taken together, these results suggest the presence of distinct "activating" and "inhibitory" motifs in the C3a sequence. Response to both is in balance under physiologic conditions. Furthermore, present data predict that such inhibitory peptides may serve as potent agents for future therapeutic intervention.
Andrásfalvy
Márton
M
Department of Immunology, Eötvös Lorand University, Budapest, Hungary.
Péterfy
Hajna
H
Tóth
Gábor
G
Matkó
János
J
Abramson
Jakub
J
Kerekes
Krisztina
K
Vámosi
György
G
Pecht
Israel
I
Erdei
Anna
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015926:Complement C3a / Q000494:pharmacology*; D007073:Immunoglobulin E / Q000502:physiology*; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021122:Protein Subunits; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D009842:Oligopeptides; D021122:Protein Subunits; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D014443:Tyrosine; D015926:Complement C3a; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium