Cellular immune reaction in the pancreas is induced by constitutively active IκB kinase-2

Background: Activation of the nuclear factor kappa B (NF-kappa B) system is a major event in acute and chronic inflammatory processes. NF-kappa B cascades are comprised of I kappa B kinases, I kappa Bs and NF-kappa B 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 I kappa B 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 IkB 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. IKK2CA expression in the pancreas had a mosaic appearance. Ectopic IKK2CA mostly activated the classical NF-kappa B pathway. The activation level of the NF-kappa B 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 a 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 IKK2CA caused increased tissue damage compared with either IKK2CA 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 IKK2CA induced infiltrations resemble those observed in autoimmune pancreatitis, indicating a role for IKK2/NF-kappa B 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-kappa B pathway in this disease.