| Budget Amount *help |
¥3,710,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥2,800,000 (Direct Cost: ¥2,800,000)
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| Research Abstract |
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
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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
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