Fujii Yoshihito X, Fujigaya Hirofumi, Moriwaki Yasuhiro, Misawa Hidemi, Kasahara Tadashi, Grando Sergei A, Kawashima Koichiro
Department of Pharmacology, Kyoritsu College of Pharmacy, Minato-ku, Tokyo 105-8512, Japan.
J Neuroimmunol. 2007 Sep;189(1-2):69-74. doi: 10.1016/j.jneuroim.2007.07.003. Epub 2007 Aug 1.
Human and murine immune cells such as mononuclear leukocytes consisting of mainly T and B cells, bone marrow derived dendritic cells (DCs) and macrophages all express various nicotinic acetylcholine (ACh) receptor (nAChR) subunits. Activated T cells and DCs have the ability to synthesize ACh by choline acetyltransferase, suggesting the role of non-neuronal cholinergic system expressed in immune cells in the regulation of immune cell function. Stimulation of human leukemic T and B cell lines with nicotine causes a transient Ca(2+)-signaling that is antagonized by alpha-bungarotoxin, suggesting the involvement of alpha7 subunit. Furthermore, alpha7 nAChRs have been shown to negatively regulate synthesis and release of tumor necrosis factor (TNF)-alpha in macrophages. These findings suggest that immune cell function is regulated by its own non-neuronal cholinergic system, at least in part, via alpha7 nAChR-mediated pathways. In the present study, we tested the role of alpha7 nAChRs in the regulation of immune function by measuring total serum and antigen-specific IgG(1) and IgM, and production of TNF-alpha, gamma interferon (IFN-gamma) and interleukin (IL)-6 in activated spleen cells of nAChR alpha7 subunit gene knockout (alpha7 KO) and wild-type C57BL/6J mice immunized with ovalbumin (OVA). We found that serum levels of total and anti-OVA-specific IgG(1) were significantly elevated in alpha7 KO mice, though there were no significant differences in serum levels of total and anti-OVA-specific IgM between the two genotypes. Production of TNF-alpha, IFN-gamma and IL-6 in spleen cells was significantly facilitated in alpha7 KO mice. Expression of AChE mRNA was not different between the two genotypes. These results suggest that alpha7 nAChRs are involved in the regulation of cytokine production, through which modulates TNF-alpha, IFN-gamma and IL-6 productions, leading to modification of antibody production, but are not involved in expression of cholinergic components in immune cells.
人类和小鼠的免疫细胞，如主要由T细胞和B细胞组成的单核白细胞、骨髓来源的树突状细胞（DCs）和巨噬细胞，均表达多种烟碱型乙酰胆碱（ACh）受体（nAChR）亚基。活化的T细胞和DCs能够通过胆碱乙酰转移酶合成ACh，这表明免疫细胞中表达的非神经元胆碱能系统在调节免疫细胞功能中发挥作用。用尼古丁刺激人白血病T细胞和B细胞系会引起短暂的Ca(2+)信号，该信号可被α-银环蛇毒素拮抗，提示α7亚基参与其中。此外，α7 nAChRs已被证明可负向调节巨噬细胞中肿瘤坏死因子（TNF）-α的合成和释放。这些发现表明，免疫细胞功能至少部分地通过α7 nAChR介导的途径，受其自身的非神经元胆碱能系统调节。在本研究中，我们通过测量用卵清蛋白（OVA）免疫的nAChR α7亚基基因敲除（α7 KO）和野生型C57BL/6J小鼠活化脾细胞中总血清和抗原特异性IgG(1)及IgM水平，以及TNF-α、γ干扰素（IFN-γ）和白细胞介素（IL）-6的产生，来测试α7 nAChRs在免疫功能调节中的作用。我们发现，α7 KO小鼠中总血清和抗OVA特异性IgG(/)水平显著升高，尽管两种基因型之间总血清和抗OVA特异性IgM水平无显著差异。α7 KO小鼠脾细胞中TNF-α、IFN-γ和IL-6的产生显著增加。两种基因型之间乙酰胆碱酯酶（AChE）mRNA的表达无差异。这些结果表明，α7 nAChRs参与细胞因子产生的调节，通过调节TNF-α、IFN-γ和IL-6的产生，进而影响抗体产生，但不参与免疫细胞中胆碱能成分的表达。
