Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology and School of Medicine, Trinity College, Dublin 2, Ireland.
J Neuroimmunol. 2011 Mar;232(1-2):209-16. doi: 10.1016/j.jneuroim.2010.10.001. Epub 2010 Oct 30.
Systemic administration of the β(2)-adrenoceptor agonist clenbuterol induces expression of IL-1β and its negative regulators, interleukin-1 receptor antagonist (IL-1ra) and the interleukin-1 type II decoy receptor (IL-1RII) in rat brain. Clenbuterol also increases central expression of the broad spectrum anti-inflammatory cytokine interleukin-10 (IL-10) and its downstream signalling molecule, suppressor of cytokine signalling-3 (SOCS-3). Here we examine the impact of combined treatment with clenbuterol (0.5mg/kg) and the glucocorticoid dexamethasone (1mg/kg) on mRNA expression of IL-1β and the IL-1β-inducible gene iNOS, on IκBα mRNA expression and NFκB activation, and on mRNA expression of the anti-inflammatory molecules IL-1ra, IL-1RII, IL-10 and SOCS-3 in rat cortex, striatum and hippocampus. Dexamethasone inhibited induction of IL-1β and iNOS mRNA expression by clenbuterol in all three brain regions, without altering its ability to induce IL-1ra mRNA expression. In the case of IL-1RII, dexamethasone further augmented clenbuterol-induced IL-1RII mRNA expression in hippocampus and striatum. These data highlight a mechanistic dissociation between the ability of β(2)-adrenoceptor activation to induce expression of IL-1β, and its negative regulators IL-1ra and IL-1RII in the brain. Treatment with either dexamethasone or clenbuterol alone independently induced IκBα mRNA expression, and elicited a concomitant decrease in the DNA binding of NFκB in all three brain regions. In the hippocampus and striatum dexamethasone treatment did not influence the ability of clenbuterol to induce IL-10 mRNA expression. In contrast in the cortex, induction of IL-10 and SOCS-3 mRNA expression by clenbuterol administered in combination with dexamethasone was less than induced by clenbuterol alone. Overall these data indicate that combined treatment with dexamethasone and the β(2)-adrenoceptor agonist clenbuterol elicit complementary anti-inflammatory actions in the CNS. Specifically, dexamethasone inhibits expression of pro-inflammatory cytokines, whereas clenbuterol has the added benefit of promoting expression of anti-inflammatory molecules including IL-1ra, IL-1RII, IL-10 and SOCS-3.
β(2)-肾上腺素受体激动剂克仑特罗的全身给药会诱导大鼠大脑中白细胞介素-1β（IL-1β）及其负调控因子白细胞介素-1 受体拮抗剂（IL-1ra）和白细胞介素-1 型 II 型诱饵受体（IL-1RII）的表达。克仑特罗还会增加广谱抗炎细胞因子白细胞介素-10（IL-10）及其下游信号分子细胞因子信号转导抑制因子-3（SOCS-3）在中枢神经系统中的表达。在这里，我们研究了联合使用克仑特罗（0.5mg/kg）和糖皮质激素地塞米松（1mg/kg）对 IL-1β 和其诱导基因 iNOS 的 mRNA 表达、IκBα mRNA 表达和 NFκB 激活以及抗炎分子 IL-1ra、IL-1RII、IL-10 和 SOCS-3 的 mRNA 表达的影响。地塞米松抑制了克仑特罗在所有三个脑区诱导的 IL-1β 和 iNOS mRNA 表达，而不改变其诱导 IL-1ra mRNA 表达的能力。就 IL-1RII 而言，地塞米松进一步增强了克仑特罗在海马和纹状体中诱导的 IL-1RII mRNA 表达。这些数据突出了β(2)-肾上腺素受体激活诱导大脑中 IL-1β 及其负调控因子 IL-1ra 和 IL-1RII 表达之间的机制分离。单独使用地塞米松或克仑特罗治疗均可独立诱导 IκBα mRNA 表达，并导致所有三个脑区 NFκB 的 DNA 结合减少。在海马和纹状体中，地塞米松处理并不影响克仑特罗诱导 IL-10 mRNA 表达的能力。相比之下，在皮质中，与单独使用克仑特罗相比，地塞米松和克仑特罗联合治疗诱导的 IL-10 和 SOCS-3 mRNA 表达减少。总的来说，这些数据表明，地塞米松和β(2)-肾上腺素受体激动剂克仑特罗联合治疗在中枢神经系统中产生互补的抗炎作用。具体而言，地塞米松抑制促炎细胞因子的表达，而克仑特罗则具有促进抗炎分子表达的额外益处，包括 IL-1ra、IL-1RII、IL-10 和 SOCS-3。
