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

Objectives: VIP receptor has been clarified to exist on immune cells, indicating its possible involvement in immunity and inflammatory response. Therefore, we investigated the effects of VIP and selective agonists for 2 subtypes of VIP receptor (VPAC₁-R and VPAC₂-R agonist) on acute pancreatitis. Methods: Acute pancreatitis was induced in mice by 4 intraperitoneal injections of cerulein and an injection of LPS. VIP, VPAC ₁-R agonist, VPAC₂-R agonist, or secretin (5 nmol/body) was administered 30 minutes before and after the administration of LPS. Serum amylase and cytokine levels were determined, and histologic changes were evaluated. In vitro, IL-6 and TNF-α 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: VPAC ₁-R agonist significantly decreased serum amylase, IL-6, and TNF-α, whereas VPAC₂-R agonist markedly increased serum amylase. Histologically, VIP and VPAC₁-R agonist attenuated the severity of 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-α levels in a dose-dependent manner. Conclusion: VIP attenuated the experimental acute pancreatitis enzymatically and morphologically by inhibiting proinflammatory cytokine production from monocytes mainly through the VPAC₁-R.