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

Abstract

Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-κB target genes, including mediators of the inflammatory response such as TNF-α and ICAM-1. Indeed, inhibition of TNF-α activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-κB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease. IntroductionThe NF-κB transcription factors play a prominent role in controlling the integration of innate immunity into the inflammatory response and adaptive immunity. The activation and nuclear translocation of NF-κB induces the expression of a diverse range of proinflammatory genes, including chemokines, cytokines, and cell adhesion molecules, all necessary for an effective defense response to infectious agents. However, failure to terminate or resolve the inflammatory response has detrimental consequences for the organism. As NF-κB is one of the main transcriptional regulators of inflammation, pathological activation of NF-κB is often associated with chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, asthma, and multiple sclerosis (1-3).NF-κB represents a family of homodimeric and heterodimeric transcription factors composed of 5 members, namely p50, p52, RelA/p65, RelB, and c-Rel. NF-κB is activated by a large number of inducers, including factors critically involved in the inflammatory response such as TNF-α, IL-1β, and microbial products. These factors activate the TNF, IL-1, Nod-like, and Toll-like receptor systems and thereby initiate signaling cascades that converge on the classical NF-κB pathway. This induces the nuclear translocation of NF-κB dimers typically composed of p50 and RelA/p65. The pivotal regulatory step in this pathway is the signal-induced phosphorylation of inhibitor of NF-κB (IκB) proteins, which are mediated by the IκB kinase (IKK) complex. In unstimulated cells, IκB proteins interact with the NF-κB proteins and inhibit their nuclear translo...

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

“…Pdx-1.tTA mice (C57BL/6) (6) and (tetO) 7 .IKK2-CA (constitutively active mutant of human IKK2) mice (NMRI) (7) were described previously. Pdx-1.tTA mice are knockin animals in which the coding sequence of tetracycline-dependent transactivator (tTA) has replaced the endogenous Pdx-1 gene, thereby rendering this mouse line heterozygous for Pdx-1 (Pdx-1 +/2 ).…”

“…Pdx-1.tTA mice are knockin animals in which the coding sequence of tetracycline-dependent transactivator (tTA) has replaced the endogenous Pdx-1 gene, thereby rendering this mouse line heterozygous for Pdx-1 (Pdx-1 +/2 ). Control mice group include wild-type and single-transgenic (tetO) 7 . IKK2-CA mice unless otherwise stated.…”

IκB Kinase/Nuclear Factor κB-Dependent Insulin-Like Growth Factor 2 (Igf2) Expression Regulates Synapse Formation and Spine Maturation via Igf2 Receptor Signaling

“…Upon activation, the IB kinase (IKK) complex composed of IKK1 (IKK␣), IKK2 (IKK␤), and NEMO (IKK␥), phosphorylates IB proteins, thereby initiating their proteasomal degradation followed by the release and nuclear translocation of active NF-B complexes (Ghosh and Karin, 2002;Scheidereit, 2006). The canonical NF-B pathway depends on IKK2 and NEMO function, and dominant-negative versions of IKK2 have been shown to efficiently block this pathway in vivo (Herrmann et al, 2005;Baumann et al, 2007).…”

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