Ngwainmbi Joy, De Dipanjana D, Smith Tricia H, El-Hage Nazira, Fitting Sylvia, Kang Minho, Dewey William L, Hauser Kurt F, Akbarali Hamid I
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298
J Neurosci. 2014 Oct 22;34(43):14243-51. doi: 10.1523/JNEUROSCI.2283-14.2014.
The gastrointestinal (GI) tract presents a major site of immune modulation by HIV, resulting in significant morbidity. Most GI processes affected during HIV infection are regulated by the enteric nervous system. HIV has been identified in GI histologic specimens in up to 40% of patients, and the presence of viral proteins, including the trans-activator of transcription (Tat), has been reported in the gut indicating that HIV itself may be an indirect gut pathogen. Little is known of how Tat affects the enteric nervous system. Here we investigated the effects of the Tat protein on enteric neuronal excitability, proinflammatory cytokine release, and its overall effect on GI motility. Direct application of Tat (100 nm) increased the number of action potentials and reduced the threshold for action potential initiation in isolated myenteric neurons. This effect persisted in neurons pretreated with Tat for 3 d (19 of 20) and in neurons isolated from Tat(+) (Tat-expressing) transgenic mice. Tat increased sodium channel isoforms Nav1.7 and Nav1.8 levels. This increase was accompanied by an increase in sodium current density and a leftward shift in the sodium channel activation voltage. RANTES, IL-6, and IL-1β, but not TNF-α, were enhanced by Tat. Intestinal transit and cecal water content were also significantly higher in Tat(+) transgenic mice than Tat(-) littermates (controls). Together, these findings show that Tat has a direct and persistent effect on enteric neuronal excitability, and together with its effect on proinflammatory cytokines, regulates gut motility, thereby contributing to GI dysmotilities reported in HIV patients.
胃肠道（GI）是HIV进行免疫调节的主要部位，会导致严重的发病率。HIV感染期间受影响的大多数胃肠道过程由肠神经系统调节。在高达40%的患者的胃肠道组织学标本中已发现HIV，并且在肠道中已报告存在病毒蛋白，包括转录反式激活因子（Tat），这表明HIV本身可能是一种间接的肠道病原体。关于Tat如何影响肠神经系统知之甚少。在这里，我们研究了Tat蛋白对肠神经元兴奋性、促炎细胞因子释放的影响及其对胃肠动力的总体作用。直接应用Tat（100 nM）可增加离体肌间神经元的动作电位数量，并降低动作电位起始阈值。这种效应在用Tat预处理3天的神经元（20个中有19个）以及从Tat(+)（表达Tat）转基因小鼠分离的神经元中持续存在。Tat增加了钠通道亚型Nav1.7和Nav1.8的水平。这种增加伴随着钠电流密度的增加和钠通道激活电压的左移。Tat增强了RANTES、IL-6和IL-1β，但未增强TNF-α。Tat(+)转基因小鼠的肠道转运和盲肠含水量也显著高于Tat(-)同窝小鼠（对照）。总之，这些发现表明Tat对肠神经元兴奋性有直接和持久的影响，并且连同其对促炎细胞因子的影响，调节胃肠动力，从而导致HIV患者中报道的胃肠动力障碍。
