Immunomodulation by adrenergic receptor : the application to stress related disease

Toll样受体（TLR）在天然免疫中起重要作用。同时，β2肾上腺素能受体（β2-adrenergicreceptor，b_2AR）是交感神经系统调节免疫系统的关键环节，但其在巨噬细胞中的作用尚不清楚。本研究证实了β_2AR和TLR信号通路之间的相互作用。TLR 4配体脂多糖（LPS）刺激可下调β_2 AR的表达。为了研究β_2 AR表达下调的生理后果，将β_2 AR表达载体（RAWar）转染巨噬细胞系RAW 264细胞。LPS刺激诱导型一氧化氮合酶（NOS II）的表达和NO的产生显着抑制RAWar细胞。LPS刺激后，细胞核因子κB（NF-κ13）的活化和NF-κB抑制因子（IκBα）的降解明显减少。LPS刺激后，RAW 264细胞中β-arrestin 2的表达也明显降低，而RAW细胞中β-arrestin 2的表达则无明显变化。 ...更多信息 ar细胞。此外，我们证明β-arrestin 2与胞质IκBα相互作用，并且抗β-arrestin 2抗体免疫共沉淀的IκBα水平在RAW 264细胞中降低，但在RAWar或RAWarr 2细胞中不降低。这些结果表明，LPS刺激信号抑制β_2AR表达，导致β-arrestin 2表达下调，从而稳定胞浆IκBα，抑制NOS II表达所必需的NF-κ B活化。LPS刺激的NO和促炎细胞因子在训练小鼠的巨噬细胞中的产生明显高于对照小鼠。同时，运动训练降低了巨噬细胞β_2AR mRNA的稳态水平。当四环素阻遏物调节的哺乳动物表达系统下调转染β_2 AR的RAWar细胞表达时，NOS Ⅱ mRNA表达显著增加，提示运动训练引起的巨噬细胞β_2 AR表达水平的变化在LPS刺激后NO产生的调节中起作用。这些结果表明，运动训练以β 2 AR依赖和非依赖的方式提高巨噬细胞的天然免疫功能。少

Toll-like receptors (TLRs) play an important role in innate immunity. Meanwhile, β2-adrenergic receptors (b_2AR) provide the key linkages for the sympathetic nervous system to regulate the immune system; however, its role in macrophages remains uncertain. Here, we demonstrated the cross-talk between β_2AR and TLR signaling pathways. β_2AR expression was down-regulated by TLR4 ligand lipopolysaccharide (LPS) stimulation. To investigate the physiological consequence of the down-regulation, the macrohage cell line, RAW264 cells were transfected with β_2AR expression vector (RAWar). LPS-stimulated inducible nitric oxide synthase (NOS II) expression and NO production were markedly suppressed in RAWar cells. The activation of nuclear factor κB (NF-κ13) and degradation of the inhibitor of NF-κB (IκBα) in response to LPS were markedly decreased in these cells. The level of β-arrestin 2, which regulates β_2AR signaling, was also reduced in RAW264 cells after stimulation with LPS, but not in RAW … More ar cells. Further, we demonstrated that β-arrestin 2 interacted with cytosolic IκBα and that the level of IκBα co-immunoprecipitated by anti-β-arrestin 2 antibodies was decreased in RAW264 cells but not in RAWar or RAWarr2 cells. These findings suggest that LPS-stimulated signals suppress β_2AR expression, leading to down-regulation of β-arrestin 2 expression, which stabilizes cytosolic IκBα and inhibits the NF-KB activation essential for NOS II expression.Next, the effects of three-week exercise training on the functions of peritoneal macrophages from BALB/c mice were investigated. LPS-stimulated NO and proinflammatory cytokine production in macrophages from trained mice was markedly higher than those from control mice. Meanwhile, exercise training decreased the steady state level of β_2AR mRNA in macrophages. When expression of transfected β_2AR in RAWar cells was downregulated by a tetracycline repressor-regulated mammalian expression system, NOS II mRNA expression was significantly increased ; this suggested that the changes in the β_2AR expression level in macrophages associated with exercise training play a role in the regulation of NO production following LPS stimulation. These findings indicate that exercise training improves macrophage innate immune function in a β_2AR-dependent and -independent manner. Less