Cellular immune reaction in the pancreas is induced by constitutively active IκB kinase-2. Issue 2 (26th July 2006)

• Record Type: Journal Article
• Authors: Aleksic, Tamara; Baumann, Bernd; Wagner, Martin; Adler, Guido; Wirth, Thomas; Weber, Christoph K
• Is Part Of: Gut. Volume 56:Issue 2(2007)
• Page Start: 227
• Page End: 236
• Publication Date: 2006-07-26
• Subjects: AIP, autoimmune pancreatitis -- IKK2, IκB kinase-2 -- NF-κB, nuclear factor κB -- RT-PCR, reverse transcription-polymerase chain reaction -- TNFα, tumour necrosis factor α; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2005.084665
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Activation of the nuclear factor κB (NF-κB) system is a major event in acute and chronic inflammatory processes. NF-κB cascades are comprised of IκB kinases, IκBs and NF-κB dimers. Little is known of the individual roles of these proteins in organ specific inflammation. The aim of the present study was to analyse the consequences of ectopic IκB kinase-2 (IKK2) activation in the pancreas of mice. Methods: Transgenic mice were generated using an inducible genetic system (tet system) to conditionally overexpress a gain of function mutant of IKK2 (tetO-IKK2-EE) in the pancreas. To achieve transgene expression in the pancreas, these animals were crossed with CMV-rtTA mice that are known to express the rtTA protein in the pancreas. Results: In these double transgenic animals, doxycycline treatment induced expression of IKK2-EE (IKK2 CA ) in pancreatic acinar cells resulting in moderate activation of the IκB kinase complex, as measured by the immune complex kinase assay, and up to 200-fold activation of the transgene expression cassette, as detected by luciferase assay. IKK2 CA expression in the pancreas had a mosaic appearance. Ectopic IKK2 CA mostly activated the classical NF-κB pathway. The activation level of the NF-κB cascade induced by IKK2 CA was considerably lower compared with that observed after supramaximal caerulein stimulation but still led to the formation of leucocyte infiltrates first observed after 4 weeks of doxycycline stimulation with a maximum after 8–12 weeks. The infiltrates were mainly composed of B lymphocytes and macrophages. Increased mRNA levels of tumour necrosis factor α and RANTES were detected in pancreatic acinar cells. However, only minor damage to pancreatic tissue was observed. A combination of supramaximal caerulein stimulation with induction of IKK2 CA caused increased tissue damage compared with either IKK2 CA or caerulein alone. Conclusions: Our observations suggest that the role of IKK2 activation in pancreatic acini is to induce leucocyte infiltration, but at a moderate level of activation it is not sufficient to induce pancreatic damage in mice. The IKK2 CA induced infiltrations resemble those observed in autoimmune pancreatitis, indicating a role for IKK2/NF-κB in this disease. IKK2 CA in pancreatic acinar cells increases tissue damage of secretagogue induced experimental pancreatitis underlining the proinflammatory role of the IKK/NF-κB pathway in this disease.