Guo Chang-Jiang, Douglas Steven D, Lai Jian-Ping, Pleasure David E, Li Yuan, Williams Marge, Bannerman Peter, Song Li, Ho Wen-Zhe
Division of Allergy and Immunology, Joseph Stokes Jr. Research Institute of The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA.
J Neurochem. 2003 Mar;84(5):997-1005. doi: 10.1046/j.1471-4159.2003.01609.x.
Chemokines are important mediators in immune responses and inflammatory processes of neuroimmunologic and infectious diseases. Although chemokines are expressed predominantly by cells of the immune system, neurons also express chemokines and chemokine receptors. We report herein that human neuronal cells (NT2-N) produce macrophage inflammatory protein-1alpha and -1beta (MIP-1alpha and MIP-1beta), which could be enhanced by interleukin (IL)-1beta at both mRNA and protein levels. The addition of supernatants from human peripheral blood monocyte-derived macrophage (MDM) cultures induced MIP-1beta mRNA expression in NT2-N cells. Anti-IL-1beta antibody removed most, but not all, of the MDM culture supernatant-induced MIP-1beta mRNA expression in NT2-N cells, suggesting that IL-1beta in the MDM culture supernatants is a major factor in the induction of MIP-1beta expression. Investigation of the mechanism(s) responsible for IL-1beta-induced MIP-1alpha and -1beta expression demonstrated that IL-1beta activated nuclear factor kappa B (NF-kappaB) promoter-directed luciferase activity in NT2-N cells. Caffeic acid phenethyl ester, a potent and specific inhibitor of activation of NF-kappaB, not only blocked IL-1beta-induced activation of the NF-kappaB promoter but also decreased IL-1beta-induced MIP-1alpha and -1beta expression in NT2-N cells. These data suggest that NF-kappaB is at least partially involved in the IL-1beta-mediated action on MIP-1alpha and -1beta in NT2-N cells. IL-1beta-mediated up-regulation of beta-chemokine expression may have important implications in the immunopathogenesis of inflammatory diseases in the CNS.
趋化因子是神经免疫和感染性疾病免疫反应及炎症过程中的重要介质。尽管趋化因子主要由免疫系统细胞表达，但神经元也表达趋化因子和趋化因子受体。我们在此报告，人类神经细胞（NT2-N）可产生巨噬细胞炎性蛋白-1α和-1β（MIP-1α和MIP-1β），白细胞介素（IL）-1β可在mRNA和蛋白水平增强其表达。添加人外周血单核细胞衍生巨噬细胞（MDM）培养上清液可诱导NT2-N细胞中MIP-1β mRNA表达。抗IL-1β抗体可去除大部分但非全部MDM培养上清液诱导的NT2-N细胞中MIP-1β mRNA表达，这表明MDM培养上清液中的IL-1β是诱导MIP-1β表达的主要因素。对IL-1β诱导MIP-1α和-1β表达的机制研究表明，IL-1β可激活NT2-N细胞中核因子κB（NF-κB）启动子驱动的荧光素酶活性。咖啡酸苯乙酯是一种强效且特异性的NF-κB激活抑制剂，它不仅可阻断IL-1β诱导的NF-κB启动子激活，还可降低IL-1β诱导的NT2-N细胞中MIP-1α和-1β表达。这些数据表明，NF-κB至少部分参与了IL-1β对NT2-N细胞中MIP-1α和-1β的介导作用。IL-1β介导的β趋化因子表达上调可能在中枢神经系统炎症性疾病的免疫发病机制中具有重要意义。
