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

Aleksic, Tamara; Baumann, Bernd; Wagner, Martin; Adler, Guido; Wirth, Thomas; Weber, Christoph K.
February 2007
Gut;Feb2007, Vol. 56 Issue 2, p227
Academic Journal
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 1κB kinases, IκB5 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 κB 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 (IKK2CA) 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. IKK2CA expression in the pancreas had a mosaic appearance. Ectopic IKK2CAmostly activated the classical NF-κB pathway. The activation level of the NF-κB cascade induced by IKK2CA 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 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-κB in this disease. IKK2CA 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.


Related Articles

  • Regulated β-Cell Regeneration in the Adult Mouse Pancreas. Cano, David A.; Rulifson, Ingrid C.; Heiser, Patrick W.; Swigart, Lamorna B.; Pelengaris, Stella; German, Mike; Evan, Gerard I.; Bluestone, Jeffrey A.; Hebrok, Matthias // Diabetes;Apr2008, Vol. 57 Issue 4, p958 

    Several studies have shown that the adult pancreas possesses a limited potential for β-cell regeneration upon tissue injury. One of the difficulties in studying β-cell regeneration has been the lack of a robust, synchronized animal model system that would allow controlled regulation of...

  • Cellular Production of n-3 PUFAs and Reduction of n-6-to-n-3 Ratios in the Pancreatic β-Cells and Islets Enhance Insulin Secretion and Confer Protection Against Cytokine-Induced Cell Death. Dong Wei; Li, Jie; Shen, Miaoda; Wei Jia; Nuoqi Chen; Tao Chen; Dongming Su; Haoming Tian; Shusen Zheng; Yifan Dai; Zhao, Allan // Diabetes;Feb2010, Vol. 59 Issue 2, p471 

    OBJECTIVE--To evaluate the direct impact of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the functions and viability of pancreatic β-cells. RESEARCH DESIGN AND METHODS--We developed an mfat-1 transgenic mouse model in which endogenous production of n-3 PUFAs was achieved through...

  • Islet Formation during the Neonatal Development in Mice.  // PLoS ONE;2009, Vol. 4 Issue 11, p1 

    The article presents information on a study conducted on the formation of the islets of Langerhans during neonatal development in mice. In the study, a method was developed to monitor beta-cell proliferation and islet formation in the intact pancreas of transgenic mice in which the beta-cells...

  • The Pancreas Stem Cell Niche: A Slow Cycling Pancreatic Cell Population Localized to Cytokeratin-19 Expression in the Centro-Acinar Region. Inamdar, Nilufar; Kofmann, Alexander; Song, Woo-Jin; Theise, Neil; Hussain, Mehboob A. // Diabetes;Jun2007 Supplement 1, Vol. 56, pA427 

    Cytokeratin- 19 (CK 19) is considered to be a marker for endodermal epithelial progenitor cells. In the pancreas, CK19 expression is localized to the pancreatic ductal epithelium, where epithelial progenitors of endocrine cells are localized. Progenitor cells are considered to progress slowly...

  • L-Cysteine Administration Attenuates Pancreatic Fibrosis Induced by TNBS in Rats by Inhibiting the Activation of Pancreatic Stellate Cell. LiJuan Yang; JiaQing Shen; ShanShan He; GuoYong Hu; Jie Shen; Feng Wang; Ling Xu; WeiQi Dai; Jie Xiong; JianBo Ni; ChuanYong Guo; Rong Wan; XingPeng Wang // PLoS ONE;Feb2012, Vol. 7 Issue 2, p1 

    Background and Aims: Recent studies have shown that activated pancreatic stellate cells (PSCs) play a major role in pancreatic fibrogenesis. We aimed to study the effect of L-cysteine administration on fibrosis in chronic pancreatitis (CP) induced by trinitrobenzene sulfonic acid (TNBS) in rats...

  • Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes. Yamamoto, Kyohei; Hashimoto, Hitoshi; Tomimoto, Shuhei; Shintani, Norihito; Miyazaki, Jun-ichi; Tashiro, Fumi; Aihara, Hiroyuki; Nammo, Takao; Li, Ming; Yamagata, Kazuya; Miyagawa, Jun-ichiro; Matsuzawa, Yuji; Kawabata, Yuki; Fukuyama, Yuji; Koga, Kazumi; Mori, Wakaba; Tanaka, Kazuhiro; Matsuda, Toshio; Baba, Akemichi // Diabetes;May2003, Vol. 52 Issue 5, p1155 

    Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP's pancreatic function in vivo, we generated...

  • Dissecting the Role of Glucocorticoids on Pancreas Development. Gesina, Emilie; Tronche, François; Herrera, Pedro; Duchene, Belinda; Tales, Willemène; Czernichow, Paul; Breant, Bernadette // Diabetes;Sep2004, Vol. 53 Issue 9, p2322 

    To determine whether glucocorticoids are involved in pancreas development, glucocorticoid treatment of rat pancreatic buds in vitro was combined with the analysis of transgenic mice lacking the glucocorticoid receptor (GR) in specific pancreatic cells. In vitro treatment of embryonic pancreata...

  • Pancreatic cancer: making progress. Flintoft, Louisa // Nature Reviews Cancer;Jan2004, Vol. 4 Issue 1, p4 

    Reports on findings of studies of genetic and cellular origins of pancreatic tumours, using transgenic mouse models. Estimated number of deaths annually due to pancreatic tumours in the United States; Ronald DePinho, Nabeel Bardeesy and colleagues' description of cooperative roles for lesions...

  • Inhibition of T cell homing by down-regulation of CD62L and the induction of a Th-2 response as a method to prevent acute allograft rejection in mice. Stremmel, Christian; Sienel, Wulf; Eggeling, Stephan; Passlick, Bernward; Slavin, Anthony // European Journal of Cardio-Thoracic Surgery;Aug2006, Vol. 30 Issue 2, p362 

    Abstract: Objective: For a successful immune response, migration of lymphocytes to lymphoid organs and other tissues is a key step, as the initial recognition of foreign antigens and activation of lymphocytes takes place in these organs. CD62L is a homing receptor that mediates entry of naïve...


Read the Article


Sign out of this library

Other Topics