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Retracted: Cannabinoid CB 2 receptors modulate ERK‐1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide
Author(s) -
Merighi Stefania,
Gessi Stefania,
Varani Katia,
Simioni Carolina,
Fazzi Debora,
Mirandola Prisco,
Borea Pier Andrea
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01673.x
Subject(s) - cannabinoid receptor , mapk/erk pathway , receptor , cannabinoid , microbiology and biotechnology , signalling pathways , kinase , chemistry , lipopolysaccharide , signalling , pharmacology , biology , biochemistry , immunology , agonist
BACKGROUND AND PURPOSE Cannabinoid (CB) receptor agonists have potential utility as anti‐inflammatory drugs in chronic immune inflammatory diseases. In the present study, we characterized the signal transduction pathways affected by CB 2 receptors in quiescent and lipopolysaccharide (LPS)‐stimulated murine microglia. EXPERIMENTAL APPROACH We examined the effects of the synthetic CB 2 receptor ligand, JWH‐015, on phosphorylation of MAPKs and NO production. KEY RESULTS Stimulation of CB 2 receptors by JWH‐015 activated JNK‐1/2 and ERK‐1/2 in quiescent murine microglial cells. Furthermore, CB 2 receptor activation increased p‐ERK‐1/2 at 15 min in LPS‐stimulated microglia. Surprisingly, this was reduced after 30 min in the presence of both LPS and JWH‐015. The NOS inhibitor l ‐NAME blocked the ability of JWH‐015 to down‐regulate the LPS‐induced p‐ERK increase, indicating that activation of CB 2 receptors reduced effects of LPS on ERK‐1/2 phosphorylation through NO. JWH‐015 increased LPS‐induced NO release at 30 min, while at 4 h CB 2 receptor stimulation had an inhibitory effect. All the effects of JWH‐015 were significantly blocked by the CB 2 receptor antagonist AM 630 and, as the inhibition of CB 2 receptor expression by siRNA abolished the effects of JWH‐015, were shown to be mediated specifically by activation of CB 2 receptors. CONCLUSIONS AND IMPLICATIONS Our results demonstrate that CB 2 receptor stimulation activated the MAPK pathway, but the presence of a second stimulus blocked MAPK signal transduction, inhibiting pro‐inflammatory LPS‐induced production of NO. Therefore, CB 2 receptor agonists may promote anti‐inflammatory therapeutic responses in activated microglia.