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

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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.