title: Interleukin-1β induces autophagy by affecting calcium homeostasis and trypsinogen activation in pancreatic acinar cells.
abstract: The strong up-regulation of inflammatory mediators has been reported to play a key role in acute pancreatitis (AP). Elevated serum levels of interleukin-1β (IL-1β) are associated with the development of AP. However, the precise effect and mechanism of IL-1β in AP remains obscure. In this study, we investigated the potential role and mechanism of IL-1β in AP. We measured autophagy activation in response to IL-1β in AR42J cells. The disrupting effects of IL-1β on cellular Ca(2+) were observed. To determine whether the disruption of Ca(2+) signaling has protective effects in vivo during AP, male C57BL/6 mice were treated with cerulein to induce AP. We found that the treatment of AR42J cells with IL-1β triggered autophagy and that the autophagic flux was impaired. In addition, IL-1β induced Ca(2+) release from the ER. Furthermore, the expression of the ER stress markers GRP78 and IRE1 also increased. 2APB, an antagonist of the InsP3 receptor, inhibited increased expression of autophagy markers. Subsequent biochemical assays revealed that co-culture with IL-1β could induce the activation of trypsinogen to trypsin and reduce the viability of acinar cells. Pathological changes of the pancreas were also observed in vivo. We found that the pathological injuries of the pancreas were significantly alleviated in mice co-treated with 2APB. Taken together, our results indicate that IL-1β can induce trypsin activation and decrease cellular viability in pancreatic acinar cells. These effects depend on impaired autophagy via intracellular calcium changes. Ca(2+) signaling may become a promising therapeutic target in the treatment of pancreatitis.
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Sumei
authors.initials: S
authors.lastname: Sha
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: An
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Shiqi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Xi'an No.1 Hospital Xi'an, Shaanxi Province 710002, China.
authors.forename: Xiangyun
authors.initials: X
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Chaoxu
authors.initials: C
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Quanxin
authors.initials: Q
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, The Fourth Military Medical University 127 Changle Western Road, Xi'an, Shaanxi Province 710032, China.
authors.forename: Qingchuan
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006706:Homeostasis / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D010179:Pancreas / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism*; D051381:Rats; D014162:Transfection; D014362:Trypsinogen / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D053583:Interleukin-1beta; D014362:Trypsinogen
keywords: IL-1β; autophagy; calcium; pancreatitis