Toll-like receptor stimulation differentially regulates vasoactive intestinal peptide type 2 receptor in macrophages.
Toll-like receptor stimulation differentially regulates vasoactive intestinal peptide type 2 receptor in macrophages.
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DOI：
10.1111/j.1582-4934.2009.00662.x
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发表时间：
2009-09
影响因子：
5.3
通讯作者：
Pozo D
中科院分区：
文献类型：
--
作者：
Herrera JL;Gonzalez-Rey E;Fernandez-Montesinos R;Quintana FJ;Najmanovich R;Pozo D
血管活性肠肽（Vasoactive intestinal peptide， VIP）最初是作为血管扩张性肠肽分离出来的，后来作为神经肽分离出来。在免疫系统中，VIP被描述为内源性巨噬细胞失活因子。VIP通过特异性受体以旁分泌和/或自分泌方式发挥其免疫作用。然而，对VIP 2型受体（VPAC2）在免疫系统中的分子调控机制知之甚少。我们现在报道了不同的toll样受体（TLR）配体选择性地调节VPAC2受体基因，并在巨噬细胞中显示出由关键蛋白激酶信号级联控制的基因抑制系统。VPAC2基因表达受革兰氏阳性菌（TLR2配体）和革兰氏阴性菌壁成分（TLR4配体）调控。此外，VPAC2受到严格调控：TLR2-或TLR2/6-而不是TLR2/1介导的机制负责诱导VPAC2。病毒或细菌核酸刺激TLR不改变VPAC2 mRNA水平。值得注意的是，合成的TLR7配体咪喹莫特导致VPAC2基因表达的有效上调。革兰氏阳性和革兰氏阴性细菌中存在的鞭毛蛋白对TLR5的刺激不影响VPAC2 mRNA。p38丝裂原活化蛋白激酶（MAPK）活性是tlr4介导的VPAC2基因表达诱导的原因。令人惊讶的是，我们的数据首次强烈表明，MAPK激酶1/2、PI3K/Akt下游元件，特别是jun - nh2末端激酶信号通路，对vpac2mrna诱导的严格抑制控制。
Vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator intestinal peptide, then as a neuropeptide. In the immune system, VIP is described as an endogenous macrophage-deactivating factor. VIP exerts its immunological actions in a paracrine and/or autocrine manner, through specific receptors. However, very little is known about the molecular regulation of VIP type 2 receptor (VPAC2) in the immune system. We now report that different toll-like receptor (TLR) ligands selectively regulate the VPAC2 receptor gene and show a gene repression system controlled by key protein kinase signalling cascades in macrophages. VPAC2 gene expression is regulated by gram-positive (TLR2 ligands) and gram-negative bacteria wall constituents (TLR4 ligands). Moreover, VPAC2 is tightly regulated: TLR2- or TLR2/6- but not TLR2/1-mediated mechanisms are responsible for the induction of VPAC2. TLR stimulation by viral or bacterial nucleic acids did not modify the VPAC2 mRNA levels. Remarkably, imiquimod – a synthetic TLR7 ligand – led to a potent up-regulation of VPAC2 gene expression. TLR5 stimulation by flagellin present in gram-positive and gram-negative bacteria did not affect VPAC2 mRNA. The p38 mitogen-activated protein kinase (MAPK) activity accounted for the TLR4-mediated induction of VPAC2 gene expression. Surprisingly, our data strongly suggest for the first time a tightly repressed control of VPAC2 mRNA induction by elements downstream of MAPK kinase 1/2, PI3K/Akt, and particularly Jun-NH2-terminal kinase signalling pathways.