Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, MD 20892, USA.
Neuropharmacology. 2010 Jan;58(1):208-14. doi: 10.1016/j.neuropharm.2009.07.034. Epub 2009 Jul 31.
We have examined induction of neuropeptide expression in adrenal medulla after treatment of mice with lipopolysaccharide (LPS), a model for septic shock, which activates both immune and stress responses in vivo. Messenger RNAs encoding vasoactive intestinal polypeptide (VIP) and galanin, both modulators of steroidogenesis in neighboring adrenal cortex, are up-regulated at 24 h (eight-fold for VIP and two-fold for galanin) after LPS injection, and remain elevated for the following 24 h. Up-regulation of VIP and galanin by LPS is abrogated in pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice, suggesting an interaction between LPS, or LPS-induced cytokines, and PACAP released in adrenal medulla from the splanchnic nerve. Treatment of cultured chromaffin cells with 100 nM PACAP and 10 nM tumor necrosis factor-alpha (TNF-alpha), a cytokine whose production is elevated by LPS, results in long-term synergistic up-regulation of VIP and galanin mRNA. PACAP blocks the earlier induction by TNF-alpha of mRNA encoding inhibitor of NF-kappaB alpha (I kappaB alpha), normally a negative autoregulator of TNF-alpha signaling through nuclear factor-kappaB (NF-kappaB), without affecting the induction of TNF-alpha-induced protein 3 (TNFAIP3), another NF-kappaB-dependent gene induced by TNF-alpha in chromaffin cells. By acting downstream of NF-kappaB to inhibit I kappaB alpha gene induction by TNF-alpha, PACAP may block I kappaB alpha-dependent negative autoregulation of TNF-alpha signaling through NF-kappaB, prolonging TNF-alpha-dependent signaling to neuropeptide-encoding genes in chromaffin cells. This mechanism may also underlie PACAP-dependent neuropeptide gene induction by LPS in vivo.
我们研究了脂多糖（LPS）处理小鼠后肾上腺髓质中神经肽表达的诱导，LPS 是脓毒性休克的模型，它在体内激活免疫和应激反应。编码血管活性肠肽（VIP）和甘丙肽的信使 RNA，这两种物质都是相邻肾上腺皮质中类固醇生成的调节剂，在 LPS 注射后 24 小时（VIP 上调 8 倍，甘丙肽上调 2 倍）上调，并在接下来的 24 小时内保持升高。在垂体腺苷酸环化酶激活肽（PACAP）缺陷小鼠中，LPS 诱导 VIP 和甘丙肽的上调被阻断，这表明 LPS 或 LPS 诱导的细胞因子与从内脏神经释放到肾上腺髓质的 PACAP 之间存在相互作用。用 100 nM PACAP 和 10 nM 肿瘤坏死因子-α（TNF-α）处理培养的嗜铬细胞，TNF-α 的产生被 LPS 上调，导致 VIP 和甘丙肽 mRNA 的长期协同上调。PACAP 阻断了 TNF-α诱导的 mRNA 编码核因子-κB 抑制物κB -α（IκBα）的早期诱导，IκBα 通常是 TNF-α 信号通过核因子-κB（NF-κB）的负反馈调节剂，而不影响 TNF-α诱导的蛋白 3（TNFAIP3）的诱导，TNFAIP3 是另一种在嗜铬细胞中由 TNF-α诱导的 NF-κB 依赖性基因。通过在 NF-κB 下游作用抑制 TNF-α诱导的 IκBα基因诱导，PACAP 可能通过 NF-κB 阻断 IκBα依赖性 TNF-α信号的负反馈调节，延长 TNF-α依赖的信号传递到嗜铬细胞中的神经肽编码基因。这种机制也可能是体内 LPS 依赖的 PACAP 诱导神经肽基因表达的基础。
