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

背景与目的：VIP受体已被证实存在于免疫细胞上，提示其可能参与免疫和炎症反应。因此，我们研究了VIP和VIP受体两种亚型的选择性激动剂(VPAC1-R和VPAC2-R激动剂)在急性胰腺炎中的作用。方法：采用4次注射雨蛙素和1次注射脂多糖的方法复制小鼠急性胰腺炎模型。分别于注射前和注射后30min分别给予VIP、VPAC1-R激动剂、VPAC2-R激动剂或促胰液素(5nmol/只)。测定血清淀粉酶和细胞因子水平，评价组织学变化。体外测定VIP、VPAC1-R激动剂和VPAC2-R激动剂刺激下脾单核细胞产生IL-6和TNF-α的量，并检测单核细胞VPAC1-R和VPAC2-RmRNA的表达。结果：VPAC1-R激动剂显著降低血清淀粉酶、IL-6和TNF-α，而VPAC2-R激动剂显著升高血清淀粉酶。组织学上，VIP和VPAC1-R激动剂可减轻胰腺炎，而VPAC2-R激动剂或促胰液素无明显作用。在体外，VPAC1-R和VPAC2-R在单核细胞中有明显的表达。在内毒素刺激下，VIP呈先降低单核细胞产生IL-6，然后在高浓度时增强的双相模式。VPAC1-R激动剂降低IL-6水平，而VPAC2-R激动剂升高IL-6水平，呈剂量依赖关系。VPAC1-R激动剂以剂量依赖方式降低肿瘤坏死因子-α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，从而在酶和形态上减轻实验性急性胰腺炎。

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.