International Immunology Advance Access originally published online on July 24, 2008
International Immunology 2008 20(10):1239-1245; doi:10.1093/intimm/dxn083
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C3a-derived peptide binds to the type I Fc
R and inhibits proximal-coupling signal processes and cytokine secretion by mast cells
1 Department of Immunology, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest, Hungary
2 Department of Medical Chemistry, University of Szeged, Szeged, Hungary
3 Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
4 Immunology Research Group of the Hungarian Academy of Sciences at Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest, Hungary
Correspondence to: A. Erdei; E-mail: anna.erdei{at}freemail.hu
A peptide with the natural sequence derived from the complement component C3a, designated C3a7, and C3a9, having a modified sequence of that, was previously shown to inhibit the high-affinity IgER (Fc
RI)-induced secretory response of both mucosal and serosal-type mast cells. In addition, several processes that couple the FcRI stimulus to the cellular response were all suppressed in the presence of these peptides. Here, we show that peptide C3a9 binds to the FcRI on the surface of unperturbed mast cells (rat mucosal-type RBL-2H3 cell line) and remains bound even after FcRI–IgE aggregation by antigen as assessed by confocal microscopy. Moreover, that peptide interferes the initial steps of FcRI-coupling network. Namely, peptide binding to the FcRI β-chain interrupts this chain’s association with both src family protein tyrosine kinases Lyn and Fyn and enhances the internalization of the receptor. C3a9 was further found to inhibit the phosphorylation of two members of the mitogen-activated protein kinase family, extracellular signal-regulated kinase (ERK) and p38. Although ERK is usually activated via the ras–raf–mitogen-activated protein kinase/ERK kinase (MEK) pathway, our results show that C3a9 has no effect on the c-raf phosphorylation, suggesting that this complement-derived peptide inhibits ERK activation via an alternative route. C3a9 also inhibits the late-phase response to FcRI stimulus of bone marrow-derived mast cells, reducing secretion of the inflammatory cytokines IL-6 and tumor necrosis factor-
. Taken together, the consequence of its interference with the earliest steps of FcRI stimulus-response coupling and the C3a-derived peptide inhibits both the immediate and the late-phase responses of mast cells.
Keywords: complement, FcRI, mast cell, signal transduction
Transmitting editor: A. Falus
Received 18 April 2008, accepted 26 June 2008.