Abstract |
Neutrophil migration to inflamed sites is crucial for both the initiation of inflammation and resolution of infection, yet these cells are involved in perpetuation of different chronic inflammatory diseases. Gastrin-releasing peptide (GRP) is a neuropeptide that acts through G protein coupled receptors (GPCRs) involved in signal transmission in both central and peripheral nervous systems. Its receptor, gastrin-releasing peptide receptor (GRPR), is expressed by various cell types, and it is overexpressed in cancer cells. RC-3095 is a selective GRPR antagonist, recently found to have antiinflammatory properties in arthritis and sepsis models. Here we demonstrate that i.p. injection of GRP attracts neutrophils in 4 h, and attraction is blocked by RC-3095. Macrophage depletion or neutralization of TNF abrogates GRP-induced neutrophil recruitment to the peritoneum. In vitro, GRP-induced neutrophil migration was dependent on PLC-β2, PI3K, ERK, p38 and independent of Gαi protein, and neutrophil migration toward synovial fluid of arthritis patients was inhibited by treatment with RC-3095. We propose that GRPR is an alternative chemotactic receptor that may play a role in the pathogenesis of inflammatory disorders.
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Authors | Rafael Sanguinetti Czepielewski, Bárbara Nery Porto, Lucas Bortolotto Rizzo, Rafael Roesler, Ana Lúcia Abujamra, Larissa Garcia Pinto, Gilberto Schwartsmann, Fernando de Queiroz Cunha, Cristina Bonorino |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 109
Issue 2
Pg. 547-52
(Jan 10 2012)
ISSN: 1091-6490 [Electronic] United States |
PMID | 22203955
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cytokines
- Peptide Fragments
- Receptors, Bombesin
- bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-
- Gastrin-Releasing Peptide
- Bombesin
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Topics |
- Analysis of Variance
- Animals
- Bombesin
(analogs & derivatives, pharmacology)
- Chemotaxis
(drug effects, immunology)
- Cytokines
(metabolism)
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Gastrin-Releasing Peptide
(administration & dosage, immunology)
- Humans
- Inflammation
(immunology)
- Macrophages
(immunology)
- Mice
- Mice, Inbred C57BL
- Monocytes
(immunology)
- Neutrophils
(drug effects, immunology)
- Peptide Fragments
(pharmacology)
- Receptors, Bombesin
(antagonists & inhibitors, immunology, metabolism)
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