Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin

Muili, Kamaldeen; Jin, Shunqian; Orabi, Abrahim I.; Eisses, John F.; Javed, Tanveer A.; Le, Tianming; Bottino, Rita; Jayaraman, Thottala; Husain, Sohail Z.

doi:10.1074/jbc.m113.471425

Cited by 36 publications

(25 citation statements)

References 81 publications

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“…Further, the shape of the Ca 2+ signal in most cells mimicked a high amplitude peak plateau, which is a characteristic pathological signal that precedes acinar cell injury and pancreatitis 25, 26, 48–53 and which would favor calcineurin activation 54 . A recent report demonstrated that a long incubation (of 4 hr) with ioversol, a RC that is similar to the iohexol and iopamidol we used, caused a slow, globalized increase in baseline cytosolic Ca 2+ levels in the NRK-52E renal cell line 55 .…”

Section: Discussionmentioning

confidence: 94%

“…Among the putative targets of Ca 2+ in pancreatitis, which include the MPTP and kinases, the Ca 2+ -activated serine/threonine phosphatase calcineurin has been implicated as a critical mediator of acinar injury and pancreatic inflammation 16, 38, 53, 58, 59 . Calcineurin is a dimer formed by a catalytic A subunit (CnA) and a regulatory B subunit (CnB) 60–62 .…”

Section: Discussionmentioning

confidence: 99%

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Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin

Jin

Orabi

et al. 2015

Gastroenterology

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Background & Aims Radiocontrast agents are required for radiographic procedures, but these agents can injure tissues by unknown mechanisms. We investigated whether exposure of pancreatic tissues to radiocontrast agents during endoscopic retrograde cholangiopancreatography (ERCP) causes pancreatic inflammation, and studied the effects of these agents on human cell lines and in mice. Methods We exposed mouse and human acinar cells to the radiocontrast agent iohexol (Omnipaque) and measured intracellular release of Ca2+, calcineurin activation (using a luciferase reporter), activation of nuclear factor-κB (NF-κB, using a luciferase reporter), and cell necrosis (via propidium iodide uptake). We infused the radiocontrast agent into the pancreatic ducts of wild type mice (C57BL/6) to create a mouse model of post-ERCP pancreatitis; some mice were given intraperitoneal injections of the calcineurin inhibitor FK506 before and after infusion of the radiocontrast agent. CnAβ−/− mice were also used. This experiment was also performed in mice given infusions of AAV6-NF-κB-luciferase, to assess activation of this transcription factor in vivo. Results Incubation of mouse and human acinar cells, but not HEK293 or COS7 cells, with iohexol led to a peak and then plateau in Ca2+ signaling, along with activation of the transcription factors NF-κB and NFAT. Suppressing Ca2+ signaling or calcineurin with BAPTA, cyclosporine A, or FK506 prevented activation of NF-κB and acinar cell injury. Calcineurin Aβ-deficient mice were protected against induction of pancreatic inflammation by iohexol. The calcineurin inhibitor FK506 prevented contrast-induced activation of NF-κB in pancreata of mice; this was observed by live imaging of mice given infusions of AAV6- NF-kB-luciferase. Conclusions Radiocontrast agents cause pancreatic inflammation in mice, via activation of NF-κB, Ca2+ signaling, and calcineurin. Calcineurin inhibitors might be developed to prevent post-ERCP pancreatitis in patients.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin

Jin

Orabi

et al. 2015

Gastroenterology

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“…A growing body of evidence suggests that the NF-B-dependent pathway is critical in the development and persistence of pancreatic inflammation and injury (36,(41)(42)(43)(44). Thus, NF-B is an attractive target for pharmacological intervention and being able to monitor the NF-B-dependent pathway under various pathological states would facilitate the validation of novel therapeutic agents and approaches.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Imaging of Pancreatic Nuclear Factor κB (NF-κB) Activation in Live Mice Using Adeno-associated Virus (AAV) Infusion and Bioluminescence

Orabi

Sah

Javed

et al. 2015

Journal of Biological Chemistry

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Background: NF-B is an important signaling molecule in the development of acute pancreatitis. Results: Adeno-associated virus-NF-B-luciferase-infused mice showed a 77-and 140-fold increase in pancreas-specific NF-B bioluminescence following caerulein and caerulein ϩ LPS pancreatitis, respectively. Conclusion: NF-B activation can be examined in a live, dynamic fashion during pancreatic inflammation. Significance: This technique offers a valuable tool to study real-time activation of NF-B in vivo.

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“…In addition, several targets of aberrant acinar cell Ca 2ϩ following bile acid exposure have been suggested and include mitochondria (44,45), sarco/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA) pumps (7), and a host of Ca 2ϩ -mediated proteins (28,42). We have shown that the serine/ threonine phosphatase calcineurin is activated in response to Ca 2ϩ generated by bile acid exposure (42) and that calcineurin plays an important role in regulating bile acid-induced NF-B activation (46).…”

Section: Discussionmentioning

confidence: 99%

Cluster of Differentiation 38 (CD38) Mediates Bile Acid-induced Acinar Cell Injury and Pancreatitis through Cyclic ADP-ribose and Intracellular Calcium Release

Orabi¹,

Muili²,

Javed³

et al. 2013

Journal of Biological Chemistry

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Aberrant Ca2+ signals within pancreatic acinar cells are an early and critical feature in acute pancreatitis, yet it is unclear how these signals are generated. An important mediator of the aberrant Ca2+ signals due to bile acid exposure is the intracellular Ca2+ channel ryanodine receptor. One putative activator of the ryanodine receptor is the nucleotide second messenger cyclic ADP-ribose (cADPR), which is generated by an ectoenzyme ADP-ribosyl cyclase, CD38. In this study, we examined the role of CD38 and cADPR in acinar cell Ca2+ signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38−/−). Cytosolic Ca2+ signals were imaged using live time-lapse confocal microscopy in freshly isolated mouse acinar cells during perifusion with the bile acid taurolithocholic acid 3-sulfate (TLCS; 500 μm). To focus on intracellular Ca2+ release and to specifically exclude Ca2+ influx, cells were perifused in Ca2+-free medium. Cell injury was assessed by lactate dehydrogenase leakage and propidium iodide uptake. Pretreatment with either nicotinamide (20 mm) or the cADPR antagonist 8-Br-cADPR (30 μm) abrogated TLCS-induced Ca2+ signals and cell injury. TLCS-induced Ca2+ release and cell injury were reduced by 30 and 95%, respectively, in Cd38-deficient acinar cells compared with wild-type cells (p < 0.05). Cd38-deficient mice were protected against a model of bile acid infusion pancreatitis. In summary, these data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca2+ signaling.

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Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin

Cited by 36 publications

References 81 publications

Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin

Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin

Dynamic Imaging of Pancreatic Nuclear Factor κB (NF-κB) Activation in Live Mice Using Adeno-associated Virus (AAV) Infusion and Bioluminescence

Cluster of Differentiation 38 (CD38) Mediates Bile Acid-induced Acinar Cell Injury and Pancreatitis through Cyclic ADP-ribose and Intracellular Calcium Release

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