Effects of tofacitinib and takinib on autoimmune pancreatitis in mice

Using a mouse model of autoimmune pancreatitis (AIP), we investigated two potential alternatives to steroid treatment, the transforming growth factor-ß-activated kinase 1 (TAK1) inhibitor takinib, and the Janus kinase (JAK) inhibitor tofacitinib. The drug effects were assessed histopathologically and by RNA sequencing (RNA-seq). MRL/MpJ mice that received injections of polyinosinic-polycytidylic acid developed severe AIP with inflammation, destruction of acinar tissue, and fibrosis. The steroid dexamethasone significantly attenuated the disease, while takinib or tofacitinib had no effects. In the principal component analysis of pancreatic RNA-seq data, poly I:C-injected mice treated with tofacitinib, takinib, and solvent formed a common cluster whereas completely untreated and dexamethasone-treated mice clustered separately. We conclude that inhibition of TAK1 or JAKs alone is not sufficient to improve AIP in mice. Overall design: MRL/MpJ mice received injections of polyinosinic-polycytidylic acid (poly I:C) for six weeks to trigger AIP. During the last four weeks, they were also treated with takinib (75 mg/kg body weight), tofacitinib (15 mg/kg), dexamethasone (1 mg/kg), or solvent only. RNA was isolated from pancreatic tissue and subjected to RNA seq analysis.