title: Suppression of IL-1beta expression by the Jak 2 inhibitor AG490 in cerulein-stimulated pancreatic acinar cells.
abstract: Cerulein pancreatitis is similar to human edematous pancreatitis with dysregulation of the digestive enzyme production and cytoplasmic vacuolization, the death of acinar cells, edema formation, and an infiltration of inflammatory cells into the pancreas. Cytokines are up-regulated in pancreatic acinar cells stimulated with cerulein. In various cells and tissues, Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway mediates inflammatory process. In the present study, we investigated whether the activation of Jak/Stat signaling mediates IL-1beta expression in pancreatic acinar AR42J cells stimulated with cerulein in vitro as well as the rats with cerulein pancreatitis in vivo using AG490, the Jak2 inhibitor. Activation of Jak2 and Stat3 were monitored by Western blot analysis for phosphorylated Jak2 and phosphorylated Stat3. mRNA expression and protein level of IL-1beta were determined by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbant assay (ELISA). Histological examination of pancreatic tissues were performed and serum IL-1beta levels of the rats were determined by ELISA. As a result, cerulein induced the activation of Jak2 and Stat3 as well as IL-1beta expression, which was inhibited by the treatment of AG490 in AR42J cells. In cerulein pancreatitis of the rats, edematous and inflammatory changes of the pancreas and increased serum levels of IL-1beta were suppressed by AG490 treatment. In conclusion, Jak2/Stat3 pathway may be the underlying mechanism in the pathogenesis of pancreatitis by inducing cytokines such as IL-1beta.
authors.affiliation: Department of Pharmacology, Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Yu
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Hyeyoung
authors.initials: H
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002108:Ceruletide / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D002108:Ceruletide; D053614:Janus Kinase 2