Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages:: role of IL-10 and ERK1/2 kinase signaling
Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages:: role of IL-10 and ERK1/2 kinase signaling
复制标题
激活大麻素 CB2 受体可负向调节小鼠巨噬细胞中 IL-12p40 的产生：IL-10 和 ERK1/2 激酶信号的作用
DOI：
10.1038/sj.bjp.0706215
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发表时间：
2005-06-01
影响因子：
7.3
通讯作者：
Guaza, C
中科院分区：
文献类型：
--
作者：
Correa, F;Mestre, L;Guaza, C
大麻素(CB)受体激动剂具有潜在的抗炎作用，可用于多种疾病的治疗。在本研究中，我们观察了人工合成的CB2配体JWH-133对内毒素(LPS)或泰勒氏病毒(TMEV)激活的巨噬细胞产生IL-12和IL-10的影响。2 JWH-133对脂多糖/干扰素-γ诱导的IL-12p40的释放有浓度依赖性的抑制作用(10 NM-5mM)。CB2拮抗剂SR-144528(1 MM)可显著阻断JWH-133(100nM)的作用。感染TMEV的巨噬细胞IL-12p40产生增加，JWH-133(100 NM)激活CB2受体可抑制IL-12p40的产生。3 JWH-133(100 NM)对IL-12p40产生的抑制作用可能与细胞外调节激酶(ERK1/2)信号转导有关：(1)JWH-133对ERK1/2的激活程度高于内毒素诱导的激活水平；4 JWH-133(10 nM-5 mM)激活CB2受体促进巨噬细胞释放IL-10，加入SR144558(1mU/mM)可完全阻断JWH(100 NM)的作用。内源性IL-10在IL-12的产生中起着调节作用。在没有或存在JWH-133的情况下，用中和抗体阻断IL-10可增加内毒素激活的巨噬细胞分泌IL-12p40。相反，外源性mIL-10的加入减少了内毒素对IL-12p40的分泌。
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 CB2 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 nM-5 mu M) of LPS/IFN-gamma induced IL-12p40 release. The effect of JWH-133 (100 nM) was significantly blocked by the CB2 antagonist SR-144528 ( 1 mM). Macrophages infected with TMEV increased IL-12p40 production and activation of CB2 receptors by JWH-133 ( 100 nM) inhibited it.3 The inhibitory effect of JWH-133 ( 100 nM) 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 CB2 receptors by JWH-133 (10 nM-5 mM) enhanced IL-10 release by LPS/IFN-gamma-activated macrophages and addition of SR144558(1 mu M) totally blocked the effect of JWH (100 nM).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.