Small-Interference RNA Gene Knockdown of Pancreatitis-Associated Proteins in Rat Acute Pancreatitis

Lin, Yinyao; Viterbo, Domenico; Mueller, Cathy M.; Stanek, Albert; Smith‐Norowitz, Tamar A.; Drew, Hazel; Wadgaonkar, Raj; Zenilman, Michael E.; Bluth, Martin H.

doi:10.1097/mpa.0b013e31815f3933

Cited by 13 publications

(7 citation statements)

References 25 publications

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“…They reported consistent residues of GlcNAc(beta 1-6)[Gal(beta 1-3)]GalNAc alpha which ranged in size from four to nine sugar residues [22]. Similarly, variations in PAP migration have been observed in our other in vivo studies [23]. Whether or not the function of Reg or PAP is contingent on differences in glycosylation status is currently unknown.…”

Section: Discussionsupporting

confidence: 52%

Comparison of His and GST tagged versions of recombinant pancreatitis associated protein 2 in modulation of inflammatory responses

2010

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Section: Discussionsupporting

confidence: 52%

Comparison of His and GST tagged versions of recombinant pancreatitis associated protein 2 in modulation of inflammatory responses

2010

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“…17 Emerging evidence supports that PAP proteins play regulatory roles during the inflammatory process in pancreatitis. 18,19 Such studies showed the protective role of RegIII/PAPs in AP using PAP knockout mice and small interfering RNA knockdown of PAP1 and PAP3 (RegIIIγ). IL-22 was previously shown to up-regulate PAP1 in cultured pancreatic acinar cells.…”

Section: Resultsmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Regulates Pancreatic IL-22 Production and Protects Mice From Acute Pancreatitis

2012

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BACKGROUND & AIMS The type of immune response during development of acute pancreatitis (AP) determines disease severity. Pancreatic epithelial cells express the interleukin (IL)-22 receptor A1 (IL-22RA1). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates expression of IL-22. We investigated sources and role of IL-22 in the pancreas, along with the effects of AhR activation on IL-22 expression and AP progression in mice. METHODS We analyzed the effects of recombinant IL-22, a monoclonal antibody against IL-22, and agonists and antagonists of AhR in mice with AP (induced with caerulein or a choline-deficient diet supplemented with DL-ethionine) and control mice. We also analyzed transgenic mice with AhR deficiency (AhRd and AhR−/− mice). RESULTS CD4+ T cells were the main source of IL-22 in pancreatic tissues from healthy mice. During development of AP, numbers of IL-22+ CD4+ T cells were reduced, whereas IL-22RA1 was up-regulated. Consistent with high levels of IL-22RA1 expression, pancreatic acinar cells responded to IL-22 signaling via signal transducers and activators of transcription 3; administration of IL-22 reduced AP and associated lung injury in mice. AhR was required for production of IL-22 and protected mice from AP. Mice that did not respond to AhR activation developed AP, but administration of IL-22 reduced AP; blockade of IL-22 reversed the ability of activated AhR to protect against AP. CONCLUSIONS AhR activation protects mice from AP by inducing expression of IL-22. AhR therefore mediates interactions between pancreatic leukocytes and epithelial cells and might be developed as a therapeutic target.

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“…For example, Zhang and colleagues37 found that targeted inhibition of gene expression of PAPs by antisense oligodeoxyribonucleotides exacerbates the severity of AP in rats. Furthermore, they also reported that both small interfering RNA (siRNA)-mediated gene knockdown of PAP and administration of anti-Reg1 and anti-PAP2 antibodies worsens sodium taurocholate-induced pancreatitis 38 39. Using PAP/HIP (hepatocarcinoma intestine pancreas) knock-out mice, Gironella and colleagues23 found that PAP/HIP has anti-apoptotic and anti-inflammatory roles in vivo during caerulein-induced pancreatitis.…”

Section: Discussionmentioning

confidence: 99%

Reg4 protects against acinar cell necrosis in experimental pancreatitis

Shen

Cheng

et al. 2010

Gut

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Background and aims Reg4 is a recently discovered member of the regenerating gene family with distinctive expression profiles in primary cancers. To date, the physiological function of Reg4 is poorly understood. Previously, the authors found that Reg4 was markedly upregulated during acute pancreatitis (AP). The aim of this study was to investigate the role of Reg4 in experimental pancreatitis. Methods AP was induced in C57BL/6 mice by administration of either l-arginine or caerulein, and Reg4 expression was assessed by immunofluorescence, reverse transcriptase (RT)-PCR and western blot analyses. Recombinant human Reg4 protein (rReg4), heat-inactivated Reg4, neutralising antibody and vehicle were also administered to mice by subcutaneous injection. The severity of AP was determined by measuring amylase and lipase activities in the serum and histological grading. The effect of rReg4 on cell death was examined and epidermal growth factor receptor (EGFR), p-EGFR, Akt, p-Akt, Bcl-2 and Bcl-xL expression were assessed by western blot analysis of isolated murine acinar cells treated with l-arginine. Results Reg4 mRNA and protein were markedly upregulated during arginine-induced pancreatitis. Reg4 was widely expressed in residual acinar cells around the islets and regenerating metaplastic epithelium. rReg4 could protect against arginine-induced necrosis of acinar cells both in vivo and in vitro. This protective effect was also confirmed in the caerulein-induced murine model of AP. It was shown that arginine induced expression of Bcl-2 and Bcl-xL, while rReg4 upregulated Bcl-2 and Bcl-xL expression by activating the EGFR/Akt pathway. The upregulation of Bcl-xL correlated inversely with cell necrosis in isolated pancreatic acinar cells. Conclusions The data suggest that Reg4 may protect against acinar cell necrosis in experimental pancreatitis by enhancing the expression of Bcl-2 and Bcl-xL via activation of the EGFR/Akt signalling pathway.

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Small-Interference RNA Gene Knockdown of Pancreatitis-Associated Proteins in Rat Acute Pancreatitis

Cited by 13 publications

References 25 publications

Comparison of His and GST tagged versions of recombinant pancreatitis associated protein 2 in modulation of inflammatory responses

Comparison of His and GST tagged versions of recombinant pancreatitis associated protein 2 in modulation of inflammatory responses

Aryl Hydrocarbon Receptor Regulates Pancreatic IL-22 Production and Protects Mice From Acute Pancreatitis

Reg4 protects against acinar cell necrosis in experimental pancreatitis

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