Vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide inhibit tumor necrosis factor-α production in injured spinal cord and in activated microglia via a cAMP-dependent pathway
Vasoactive intestinal peptide and pituitary adenylyl cyclase-activating polypeptide inhibit tumor necrosis factor-α production in injured spinal cord and in activated microglia via a cAMP-dependent pathway
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DOI：
10.1523/jneurosci.20-10-03622.2000
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发表时间：
2000-05-15
影响因子：
5.3
通讯作者：
Jonakait, GM
中科院分区：
文献类型：
--
作者：
Kim, WK;Kan, YQ;Jonakait, GM
肿瘤坏死因子- α (tnf - α)的产生伴随着各种中枢神经系统损伤。由于神经肽血管活性肠肽（VIP）和结构相关肽垂体腺苷酸环化酶激活多肽（PACAP）在外周具有强大的抗炎作用，我们研究了这些作用是否延伸到中枢神经系统。大鼠脊髓横断后2小时内诱导tnf - α mRNA，合成的VIP受体激动剂可抑制其上调。培养的大鼠小胶质细胞被用来研究这种抑制的机制，因为小胶质细胞可能是受损中枢神经系统中tnf - α的来源。在培养中，10(-7)M VIP显著降低了脂多糖（LPS）刺激导致的tnf - α mRNA的升高，相同浓度的PACAP完全消除了tnf - α mRNA的升高。tnf - α蛋白水平在10(-7)m时被VIP或PACAP降低90%。VPAC(1)受体拮抗剂阻断VIP和PACAP的作用，PAC(1)拮抗剂阻断PACAP的作用。VIP与小胶质细胞的直接结合以及VPAC(1)和PAC(1)（但不包括VPAC(2)）受体的mrna的存在证明了受体介导的作用。VIP的作用是cAMP介导的，因为(1)福斯克林对cAMP的激活模仿了这一作用；(2) H89对PKA的抑制逆转了神经肽诱导的抑制；(3)亲脂神经肽模拟物，去亮氨酸（17）VIP (SNV)，不使用camp介导的途径，无法复制抑制作用。我们得出结论，VIP和PACAP通过camp依赖性途径抑制活化小胶质细胞tnf - α的产生。
Tumor necrosis factor-alpha (TNF-alpha) production accompanies CNS insults of all kinds. Because the neuropeptide vasoactive intestinal peptide (VIP) and the structurally related peptide pituitary adenylyl cyclase-activating polypeptide (PACAP) have potent anti-inflammatory effects in the periphery, we investigated whether these effects extend to the CNS. TNF-alpha mRNA was induced within 2 hr after rat spinal cord transection, and its upregulation was suppressed by a synthetic VIP receptor agonist. Cultured rat microglia were used to examine the mechanisms underlying this inhibition because microglia are the likely source of TNF-alpha in injured CNS. In culture, increases in TNF-alpha mRNA resulting from lipopolysaccharide (LPS) stimulation were reduced significantly by 10(-7) M VIP and completely eliminated by PACAP at the same concentration. TNF-alpha protein levels were reduced 90% by VIP or PACAP at 10(-7) M. An antagonist of VPAC(1) receptors blocked the action of VIP and PACAP, and a PAC(1) antagonist blocked the action of PACAP. A direct demonstration of VIP binding on microglia and the existence of mRNAs for VPAC(1) and PAC(1) (but not VPAC(2)) receptors argue for a receptor-mediated effect. The action of VIP is cAMP-mediated because (1) activation of cAMP by forskolin mimics the action; (2) PKA inhibition by H89 reverses the neuropeptide-induced inhibition; and (3) the lipophilic neuropeptide mimic, stearyl-norleucine(17) VIP (SNV), which does not use a cAMP-mediated pathway, fails to duplicate the inhibition. We conclude that VIP and PACAP inhibit the production of TNF-alpha from activated microglia by a cAMP-dependent pathway.