Armstrong Brian D, Hu Zhongting, Abad Catalina, Yamamoto Miya, Rodriguez Williams I, Cheng Jennifer, Tam Jimmy, Gomariz Rosa P, Patterson Paul H, Waschek James A
Mental Retardation Research Center, Neuropsychiatric Institute, The David Geffen School of Medicine, University of California at Los Angeles, Los Angeles 90024-1759, USA.
J Neurosci Res. 2003 Oct 15;74(2):240-7. doi: 10.1002/jnr.10750.
The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP) are induced strongly in neurons after several types of injury, and exhibit neuroprotective actions in vitro and in vivo. It is thought that changes in expression of neuropeptides and other molecules in injured neurons are mediated by new factors produced in Schwann and immune cells at the injury site, a loss of target-derived factors, or a combination of mediators. To begin to determine the role of the inflammatory mediators, we investigated axotomy-induced changes in VIP and PACAP gene expression in the facial motor nucleus in severe combined immunodeficient (SCID) mice, and in mice with targeted mutations in specific cytokine genes. In normal mice, VIP and PACAP mRNA was induced strongly in facial motor neurons 4 days after axotomy. The increase in PACAP mRNA was blocked selectively in SCID mice, indicating that mechanisms responsible for VIP and PACAP gene induction are not identical. The loss of PACAP gene expression in SCID mice after axotomy was fully reversed by an infusion of normal splenocytes, suggesting that PACAP mRNA induction requires inflammatory mediators. PACAP and VIP mRNA inductions, however, were maintained in mice lacking leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), and in mice lacking both receptors for tumor necrosis factor alpha (TNFalpha). The data suggest that an inflammatory response, most likely involving T lymphocytes, is necessary for the axotomy-induced increase in PACAP but not in VIP. LIF, IL-6, and TNFalpha, however, are not required for this response to injury.
神经肽血管活性肠肽（VIP）和垂体腺苷酸环化酶激活肽（PACAP）在几种类型的损伤后在神经元中被强烈诱导，并在体外和体内表现出神经保护作用。人们认为，损伤神经元中神经肽和其他分子表达的变化是由损伤部位的雪旺细胞和免疫细胞产生的新因子、靶源性因子的丧失或多种介质共同介导的。为了开始确定炎症介质的作用，我们研究了严重联合免疫缺陷（SCID）小鼠以及特定细胞因子基因有靶向突变的小鼠中，面神经运动核内轴突切断诱导的VIP和PACAP基因表达的变化。在正常小鼠中，轴突切断后4天，面神经运动神经元中VIP和PACAP mRNA被强烈诱导。在SCID小鼠中，PACAP mRNA的增加被选择性阻断，这表明负责VIP和PACAP基因诱导机制并不相同。轴突切断后SCID小鼠中PACAP基因表达的丧失通过输注正常脾细胞完全逆转，这表明PACAP mRNA的诱导需要炎症介质。然而，在缺乏白血病抑制因子（LIF）和白细胞介素-6（IL-6）的小鼠以及缺乏肿瘤坏死因子α（TNFα）两种受体的小鼠中，PACAP和VIP mRNA的诱导得以维持。这些数据表明，炎症反应，很可能涉及T淋巴细胞，对于轴突切断诱导的PACAP增加是必要的，但对VIP增加并非必要。然而，LIF、IL-6和TNFα对于这种损伤反应并非必需。
