Monday, June 1, 2009

Cannabinoid receptor type 2 activation induces anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation

Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting ERK pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction.

MKPs regulate mitogen activated protein kinases, but their role in microglial phenotype modulation is not fully understood.

Results: We used the selective CBR2 agonist JWH015, lipopolysaccharide (LPS)-stimulated cortical primary microglial cultures, western blot analyses and migration assays. JWH015 increased MKP-1 and MKP-3 expression, which in turn reduced p-ERK1/2.

These effects resulted in a significant reduction of tumor necrosis factor-alpha (TNF) expression and microglial migration. We confirmed the causative link of these findings by using MKP inhibitors.

We found that the selective inhibition of MKP-1 by Ro-31-8220 and PSI2106, did not affect p-ERK expression in LPS+JWH015-treated microglia. However, the inhibition of both MKP-1 and MKP-3 by triptolide induced an increase in p-ERK expression and in microglial migration using LPS+JWH015-treated microglia.

Conclusions: Our results uncover a cellular microglial pathway triggered by CBR2 activation.

These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.

Author: Edgar Alfonso Romero-SandovalRyan HorvathRussell LandryJoyce DeLeo
Credits/Source: Molecular Pain 2009, 5:25

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