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Inhibitory effects of C4a on chemoattractant and secretagogue functions of the other anaphylatoxins via Gi protein-adenylyl cyclase inhibition pathway in mast cells.
MedLine Citation:
PMID:  22155625     Owner:  NLM     Status:  Publisher    
A recombinant complement anaphylatoxin, C4a, inhibited chemotaxis, respiratory burst and histamine release in mast cell-like HMC-1 cells that were treated with recombinant C5a anaphylatoxin. C4a also inhibited histamine release from HMC-1 cells that were induced by recombinant C3a. The inhibition of C5a- and C3a-induced leukocyte reactions by C4a was recapitulated in peripheral blood CD133(+) cell-derived differentiated mast cells. In HMC-1 cells, C4a inhibited cytoplasmic Ca(2+) influx, an event that precedes anaphylatoxin-induced chemotactic and secretary responses. A conditioned medium of HMC-1 cells after shortly treated with C4a also inhibited the anaphylatoxin-induced Ca(2+) influx even after removal of C4a, indicating that the effect of C4a is to liberate an autocrine inhibitor from the mast cells. The inhibitor secretion by C4a was prevented with pertussis toxin or with a phosphodiesterase inhibitor. Conversely, an adenylyl cyclase inhibitor reproduced the effect of C4a. C4a decreased the intracellular cyclic AMP concentration of HMC-1 cells, indicating that C4a elicited the Gi protein-adenylyl cyclase inhibition pathway. Neither C4a nor the conditioned medium, however, inhibited Ca(2+) influx and respiratory burst in C5a- or C3a-stimulated peripheral neutrophils, suggesting that these cells lack this inhibitory system. Additionally, in HMC-1 cells, C4a did not inhibit Ca(2+)-independent, Leu72Gln-C5a-stimulated chemotactic response. In agreement with this finding, C4a treatment inhibited ERK1/2 phosphorylation in HMC-1 cells stimulated with other anaphylatoxins but did not inhibit p38MAPK phosphorylation in cells stimulated with Leu72Gln-C5a. Taken together, these findings suggest that the autocrine inhibitory effect elicited by C4a is attributed to interruption of Ca(2+)-dependent intracellular signaling pathway.
Peiyu Xie; Hiroshi Nishiura; Umeko Semba; Jun Chen; Rui Zhao; Akihiko Kuniyasu; Tetsuro Yamamoto
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-6
Journal Detail:
Title:  International immunopharmacology     Volume:  -     ISSN:  1878-1705     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100965259     Medline TA:  Int Immunopharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier B.V.
Department of Molecular Pathology, Faculty of Life Science, Kumamoto University Graduate School, Kumamoto, Japan.
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