Delgado Mario
Departamento Biologia Celular, Facultad de Biologia, Universidad Complutense, 28040, Madrid, Spain.
Biochem Biophys Res Commun. 2002 Oct 11;297(5):1181-5. doi: 10.1016/s0006-291x(02)02305-7.
The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of pro-inflammatory factors, mainly mediated through the inhibition of NF-kappaB nuclear translocation and DNA binding. An additional regulatory element in the NF-kappaB transcriptional activity is the coactivator CBP, which links p65 with components of the basal transcriptional machinery. The present report demonstrates that VIP and PACAP inhibit the formation of p65/CBP complexes and that this event is directly related to the neuropeptide inhibition of NF-kappaB transcriptional activity. Since CBP is in limiting amounts in the nucleus and is capable of interacting with several transcriptional factors, competition for CBP provides another mechanism for transcriptional regulation. VIP and PACAP increase CBP-binding to CREB, replacing p65/CBP with CREB/CBP complexes in activated microglia. This is due to VIP/PACAP-induced increases in CREB phosphorylation/activation and is mediated through the specific VPAC1 receptor and the cAMP/PKA pathway. The VIP/PACAP interference with the p65/CBP interaction in activated microglia may represent a significant element in the regulation of the inflammatory response in the CNS by the endogenous neuropeptides.
血管活性肠肽（VIP）和垂体腺苷酸环化酶激活多肽（PACAP）这两种免疫调节神经肽，作为活化小胶质细胞的抗炎因子，通过抑制促炎因子的产生发挥作用，主要是通过抑制核因子κB（NF-κB）的核转位和DNA结合来介导。NF-κB转录活性中的另一个调节元件是共激活因子CBP，它将p65与基础转录机制的成分联系起来。本报告表明，VIP和PACAP抑制p65/CBP复合物的形成，并且这一事件与神经肽对NF-κB转录活性的抑制直接相关。由于CBP在细胞核中的量有限且能够与多种转录因子相互作用，对CBP的竞争提供了另一种转录调节机制。VIP和PACAP增加CBP与CREB的结合，在活化的小胶质细胞中用CREB/CBP复合物取代p65/CBP复合物。这是由于VIP/PACAP诱导CREB磷酸化/激活增加，并且通过特异性VPAC1受体和cAMP/PKA途径介导。VIP/PACAP对活化小胶质细胞中p65/CBP相互作用的干扰可能是内源性神经肽调节中枢神经系统炎症反应的一个重要因素。
