title: Cellular immune reaction in the pancreas is induced by constitutively active IkappaB kinase-2.
abstract: BACKGROUND
  Activation of the nuclear factor kappaB (NF-kappaB) system is a major event in acute and chronic inflammatory processes. NF-kappaB cascades are comprised of IkappaB kinases, IkappaBs and NF-kappaB 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 IkappaB 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 IkappaB 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-kappaB pathway. The activation level of the NF-kappaB 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 alpha 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-kappaB 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-kappaB pathway in this disease.
authors.affiliation: Department of Medicine I, Ulm University, Robert-Koch Strasse 8, D-89081 Ulm, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Aleksic
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
authors.forename: Martin
authors.initials: M
authors.lastname: Wagner
authors.forename: Guido
authors.initials: G
authors.lastname: Adler
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Christoph K
authors.initials: CK
authors.lastname: Weber
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002108:Ceruletide / Q000276:immunology; D018946:Chemokine CCL5 / Q000032:analysis; D004318:Doxycycline / Q000276:immunology; D004789:Enzyme Activation; D015870:Gene Expression / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology*; D007150:Immunohistochemistry / Q000379:methods; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D019076:Transgenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D018946:Chemokine CCL5; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002108:Ceruletide; D008156:Luciferases; D051550:I-kappa B Kinase; D004318:Doxycycline