VIP attenuation of the severity of experimental pancreatitis is due to VPAC1 receptor mediated inhibition of cytokine production

背景与目的：已证实VIP受体存在于免疫细胞上，提示其可能参与免疫和炎症反应。因此，我们研究了VIP和VIP受体两种亚型（VPAC1-R和VPAC2-R激动剂）的选择性激动剂对急性胰腺炎的影响。方法：四次腹腔注射小糖蛋白和一次LPS诱导小鼠急性胰腺炎。LPS给药前后30分钟分别给药VIP、VPAC1-R激动剂、VPAC2-R激动剂或分泌素（5nmol/体）。测定血清淀粉酶和细胞因子水平，评价组织学变化。在体外实验中，分别用VIP、VPAC1-R激动剂和VPAC2-R激动剂刺激LPS刺激脾脏单核细胞产生IL-6和TNF-a，并检测单核细胞中VPAC1-R和VPAC2-R mRNA的表达。结果：VPAC1-R激动剂显著降低血清淀粉酶、IL-6和TNF-a，而VPAC2-R激动剂显著升高血清淀粉酶。组织学上，VIP和VPAC1-R激动剂均能减轻胰腺炎，但VPAC2-R激动剂或分泌素无明显作用。体外单核细胞明显表达VPAC1-R和VPAC2-R mRNA。在LPS的刺激下，VIP呈现出一段时间内单核细胞IL-6产量下降，然后在高浓度下升高的双期模式。VPAC1-R激动剂降低IL-6水平，而VPAC2-R激动剂增加IL-6的剂量依赖性。VPAC1-R激动剂以剂量依赖性方式降低TNF-a水平。结论：VIP主要通过VPAC1-R抑制单核细胞产生促炎细胞因子，从酶和形态学上减弱实验性急性胰腺炎。

Background & Aims : VIP receptor has been clarified to exist on immune cells, indicating it is possible involvement in immunity and inflammatory response. Therefore, we investigated the effects of VIP and selective agonists for two subtypes of VIP receptor (VPAC1-R and VPAC2-R agonist) on acute pancreatitis. Methods : Acute pancreatitis was induced in mice by four intraperitoneal injections of Caerulein and an injection of LPS. VIP,VPAC1-R agonist, VPAC2-R agonist or secretin (5nmol/body) was administered 30 minutes before and after the administration of LPS. Serum amylase and cytokine levels were determined and histological changes were evaluated. In vitro, IL-6 and TNF-a production by monocytes from the spleen was determined under the stimulation of LPS with VIP,VPAC1-R agonist or VPAC2-R agonist, and the expression of VPAC1-R and VPAC2-R mRNA in monocytes was examined. Results : VPAC1-R agonist significantly decreased serum amylase, IL-6 and TNF-a whereas VPAC2-R agonist markedly increased serum amylase. Histologically, VIP and VPAC1-R agonist attenuated pancreatitis although VPAC2-R agonist or secretin showed no significant effect. In vitro, VPAC1-R and VPAC2-R mRNA were obviously expressed in monocytes. Under the stimulation with LPS,VIP presented a biphasic pattern that once decreased IL-6 production from monocytes, and then enhanced at high concentration. VPAC1-R agonist reduced IL-6 levels, whereas VPAC2-R agonist increased IL-6 dose-dependently. VPAC1-R agonist reduced TNF-a levels in a dose dependent manner. Conclusions : VIP attenuated the experimental acute pancreatitis enzymatically and morphologically by inhibiting pro-inflammatory cytokine production from monocytes mainly through the VPAC1-R.