2',3-dihydroxy-5-methoxybiphenyl suppresses fMLP-induced superoxide anion production and cathepsin G release by targeting the ß-subunit of G-protein in human neutrophils.
Eur J Pharmacol
; 829: 26-37, 2018 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-29601810
ABSTRACT
This study investigates the effect and the underlying mechanism of 2',3-dihydroxy-5-methoxybiphenyl (RIR-2), a lignan extracted from the roots of Rhaphiolepis indica (L.) Lindl. ex Ker var. tashiroi Hayata ex Matsum. & Hayata (Rosaceae), on N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced respiratory burst and cathepsin G in human neutrophils. Signaling pathways regulated by RIR-2 which modulated fMLP-induced respiratory burst were evaluated by an interaction between ß subunit of G-protein (Gß) with downstream signaling induced by fMLP and by immunoblotting analysis of the downstream targets of Gß-protein. RIR-2 inhibited fMLP-induced superoxide anion production (IC502.57⯱â¯0.22⯵M), cathepsin G release (IC5018.72⯱â¯3.76⯵M) and migration in a concentration dependent manner. RIR-2 specifically suppresses fMLP-induced Src family kinases phosphorylation by inhibiting the interaction between Gß-protein with Src kinases without inhibiting Src kinases activities, therefore, RIR-2 attenuated the downstream targets of Src kinase, such as phosphorylation of Raf/ERK, AKT, P38, PLCγ2, PKC and translocation Tec, p47ph°x and P40ph°x from the cytosol to the inner leaflet of the plasma membrane. Furthermore, RIR-2 attenuated fMLP-induced intracellular calcium mobilization by inhibiting the interaction between Gß-protein with PLCß2. RIR-2 was not a competitive or allosteric antagonist of fMLP. On the contrary, phorbol 12-myristate 13-acetate (PMA)-induced phosphorylation of Src, AKT, P38, PKC and membrane localization of p47ph°x and P40ph°x remained unaffected. RIR-2 specifically modulates fMLP-mediated neutrophil superoxide anion production and cathepsin G release by inhibiting the interaction between Gß-protein with downstream signaling which subsequently interferes with the activation of intracellular calcium, PLCγ2, AKT, p38, PKC, ERK, p47ph°x and p40phox.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Lignanas
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Superóxidos
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Catepsina G
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N-Formilmetionina Leucil-Fenilalanina
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Neutrófilos
Limite:
Humans
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2018
Tipo de documento:
Article