Activation of cannabinoid CB 2 receptor negatively regulates IL‐12p40 production in murine macrophages: role of IL‐10 and ERK1/2 kinase signaling

1 Cannabinoid (CB) receptor agonists have potential utility as anti‐inflammatory drugs for the treatment of many disease conditions. In the present study, we investigated the effects of the synthetic CB 2 ligand, JWH‐133 on the production of interleukins (ILs), IL‐12 and IL‐10 by lipopolyssacharide (LPS) or Theiler's virus (TMEV)‐activated macrophages. 2 JWH‐133 evoked a concentration‐related inhibition (10 n M –5  μ M ) of LPS/IFN‐γ induced IL‐12p40 release. The effect of JWH‐133 (100 n M ) was significantly blocked by the CB 2 antagonist SR‐144528 (1  μ M ). Macrophages infected with TMEV increased IL‐12p40 production and activation of CB 2 receptors by JWH‐133 (100 n M ) inhibited it. 3 The inhibitory effect of JWH‐133 (100 n M ) on IL‐12p40 production may involve extracellular‐regulated kinase (ERK1/2) signaling: (i) JWH‐133 induced a greater and sustained activation of ERK1/2 kinase in comparison with the level of activation observed following LPS; (ii) the inhibition of ERK1/2 by the specific inhibitor PD98059 increased LPS‐induced IL‐12p40 production in the presence or absence of JWH‐133 suggesting a negative regulation of ERK pathway on IL‐12p40 biosynthesis. 4 Activation of CB 2 receptors by JWH‐133 (10 n M –5 μ M ) enhanced IL‐10 release by LPS/IFN‐ γ ‐activated macrophages and addition of SR144558 (1 μ M ) totally blocked the effect of JWH (100 n M ). 5 Inhibition of ERK by PD98059 significantly suppressed IL‐10 production by LPS‐activated macrophages. Endogenous IL‐10 plays a modulatory role in IL‐12 production. Blocking IL‐10 with neutralizing antibody resulted in increased IL‐12p40 secretion by LPS‐activated macrophages in the absence or presence of JWH‐133. In contrast, the addition of exogenous mIL‐10 reduced the secretion of IL‐12p40 in response to LPS.British Journal of Pharmacology (2005) 145 , 441–448. doi: 10.1038/sj.bjp.0706215