NF-kappaB Activation Is Key To Acute Pancreatitis

Inflammation of the pancreas (pancreatitis), which is due to the breakdown of pancreatic tissue by its own enzymes, is a common clinical problem. Activation of the signaling pathway involving NF-kappaB and the inhibitor of NF-kappaB (IKK), resulting in the expression of proinflammatory molecules, is a major event in acute pancreatitis. However, the consequences of this activation on the onset and progression of pancreatitis remain unclear. Two separate studies appearing online in advance of publication in the June print issue of the Journal of Clinical Investigation, investigate the role of this signaling pathway in pancreatitis in mice.



In the first study, Thomas Wirth and colleagues from the University of Ulm, Germany, examined mice bred to only express IKK2 in pancreatic acinar cells. They found that constitutive IKK2 expression was sufficient to induce acute pancreatitis via the activation of known NF-kappaB target genes. In the second study, Roland Schmid and colleagues from the Technical University of Munich, Germany, investigated the role of a subunit of NF-kappaB called RelA/p65 in acute pancreatitis. Selective truncation of the rela gene in pancreatic cells led to both a severe injury of the acinar cells as well as systemic complications including lung and liver damage. The authors went on to show that expression of the protective pancreas-specific protein PAP1 was dependent on RelA/p65 and able to reduce the extent of pancreatic tissue necrosis in the rela mice. The results provide evidence of a role for RelA/p65 in the protection of pancreatic acinar cells against cell death, via the upregulation of PAP1. Together, the two studies identify the IKK/NF-kappaB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response that is typical of this disease.



TITLE: Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo



AUTHOR CONTACT:

Thomas Wirth

University of Ulm, Ulm, Germany.



RELATED MANUSCRIPT:



TITLE: Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis



AUTHOR CONTACT:

Roland M. Schmid

Technical University of Munich, Munich, Germany.





JCI table of contents: May 24, 2007



Contact: Brooke Grindlinger


Journal of Clinical Investigation