Glycine minimizes murine autoimmune cholangitis and pancreatitis caused by double-stranded RNA through modulation of innate immune responses

Autoimmunity is postulated to play a pivotal role in the pathogenesis of a variety of hepato-biliary and pancreatic diseases, including primary biliary cholangitis (PBC) and autoimmune pancratitis (AIP). Glycine has been shown... [ view full abstract ]

Autoimmunity is postulated to play a pivotal role in the pathogenesis of a variety of hepato-biliary and pancreatic diseases, including primary biliary cholangitis (PBC) and autoimmune pancratitis (AIP). Glycine has been shown to prevent experimental liver injuries by attenuating hepatic innate immune responses. In this study, we evaluated the effect of glycine on double-stranded RNA-induced innate and auto-immune responses in the liver and pancreas. Methods: Female, C57Bl6 mice were fed a diet containing 5% glycine and given repeated, intra-peritoneal injections of poly I:C for up to 24w. Some mice were euthanized following a single injection of poly I:C in combination with glycine-diet. Serum alkaline phosphatase (ALP) and amylase (AMY) levels were measured, and liver and pancreas histology was assessed. Serum anti-mitochondria antibody (AMA)-M2 were detected by ELISA. Hepatic mRNA levels for TNFα, IL-1β, IL-6, IFNα and IFNβ were quantified by real time RT-PCR. Results: Overt inflammatory infiltration in the portal area, predominantly lymphocytes surrounding bile ducts, was observed in mice given repeated injections of poly I:C for 16 weeks and later. These pathological changes of cholangitis were largely ameliorated in mice fed a glycine-containing diet for 8 weeks starting from 16 weeks of poly I:C. Indeed, poly I:C-induced increases in ALP levels were markedly blunted in mice given glycine-containing diet. Repeated injections of poly I:C also elicited increases in serum AMA-M2 levels, which were also blunted significantly in mice fed a glycine-containing diet. Interestingly, repeated injections of poly I:C caused not only intrahepatic cholangitis but also pancreatitis, which was also ameliorated in glycine-fed mice almost completely. Indeed, poly I:C-induced elevations in serum AMY levels were blunted significantly in glycine-fed mice. On the other hand, a single injection of poly I:C elicited transient, swift elevations in hepatic mRNA levels for TNFα, IL-1β, and IL-6, as well as IFNα and IFNβ; however, all of these parameters were blunted significantly in mice fed a glycine-diet. Conclusions: These findings clearly indicated that dietary glycine prevents development of autoimmune-related cholangitis and pancreatitis induced by repeated injections of poly I:C, most likely through attenuating innate immune responses. It is postulated that glycine is a promising immuno-nutrient for the treatment of autoimmune hepato-pancreatic diseases including PBC and AIP.