Pancreatic T cell protein-tyrosine phosphatase deficiency ameliorates cerulein-induced acute pancreatitis

Bettaieb, Ahmed; Xi, Yannan; Hosein, Ellen; Coggins, Nicole B.; Bachaalany, Santana; Wiede, Florian; Pérez, Salvador; Griffey, Stephen M.; Sastre, Juan; Tiganis, Tony; Haj, Fawaz G.

doi:10.1186/1478-811x-12-13

Cited by 11 publications

(14 citation statements)

References 74 publications

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“…Of note, panc-TCPTP KO mice exhibit a phenotype that is comparable with obese glutathione peroxidase 1-deficient mice which display defective insulin secretion associated with oxidation of PTPs (including TCPTP) and decreased PDX1 and insulin content [40]. Further, we recently demonstrated beneficial effects of pancreatic TCPTP deficiency in mitigating cerulein-induced acute pancreatitis [23], highlighting the diverse functions of TCPTP in the exocrine and endocrine pancreas. Finally, the finding that the metabolic effects of pancreatic TCPTP deficiency are influenced by diet are relevant to human type 2 diabetes, which is known to correlate with old age and obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we demonstrated that TCPTP modulates ER stress in MIN6 beta cells and that alterations in pancreatic TCPTP expression may serve to mitigate chronic ER stress [22]. More recently, we reported that pancreatic TCPTP deficiency mitigates cerulein-induced acute pancreatitis in mice [23]. In the current study, we investigated the endocrine role of pancreatic TCPTP and its underlying molecular mechanism.…”

Section: Introductionmentioning

confidence: 92%

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Pancreatic T cell protein–tyrosine phosphatase deficiency affects beta cell function in mice

Liu

Bettaieb

et al. 2014

Diabetologia

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Aims/hypothesis T cell protein tyrosine phosphatase (TCPTP, encoded by PTPN2) regulates cytokine-induced pancreatic beta cell apoptosis and may contribute to the pathogenesis of type 1 diabetes. However, the role of TCPTP in pancreatic endocrine function and insulin secretion remains largely unknown. Methods To investigate the endocrine role of pancreatic TCPTP we generated mice with pancreas Ptpn2/TCPTP deletion (panc-TCPTP KO). Results When fed regular chow, panc-TCPTP KO and control mice exhibited comparable glucose tolerance. However, when challenged with prolonged high fat feeding panc-TCPTP KO mice exhibited impaired glucose tolerance and attenuated glucose-stimulated insulin secretion (GSIS). The defect in GSIS was recapitulated in primary islets ex vivo and after TCPTP pharmacological inhibition or lentiviral-mediated TCPTP knockdown in the glucose-responsive MIN6 beta cells, consistent with this being cell autonomous. Reconstitution of TCPTP in knockdown cells reversed the defect in GSIS demonstrating that the defect was a direct consequence of TCPTP deficiency. The reduced insulin secretion in TCPTP knockdown MIN6 beta cells was associated with decreased insulin content and glucose sensing. Furthermore, TCPTP deficiency led to enhanced tyrosyl phosphorylation of signal transducer and activator of transcription 1 and 3 (STAT 1/3), and substrate trapping studies in MIN6 beta cells identified STAT 1/3 as TCPTP substrates. STAT3 pharmacological inhibition and small interfering RNA-mediated STAT3 knockdown in TCPTP deficient cells restored GSIS to control levels, indicating that the effects of TCPTP deficiency were mediated, at least in part, through enhanced STAT3 phosphorylation and signalling. Conclusions/interpretation These studies identify a novel role for TCPTP in insulin secretion and uncover STAT3 as a physiologically relevant target for TCPTP in the endocrine pancreas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Pancreatic T cell protein–tyrosine phosphatase deficiency affects beta cell function in mice

Liu

Bettaieb

et al. 2014

Diabetologia

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“…62 Of note, PTP1B expression during the early stages of AP is comparable to that of other PTPs, such as SHP1, SHP2, 15,16 and TCPTP. 18 However, pancreatic TCPTP deficiency mitigates cerulein-induced AP in mice 18 compared with the effects of PTP1B deficiency observed herein. Thus, additional investigations into the regulation of PTPs and their contribution to AP pathogenesis are warranted.…”

Section: Discussionmentioning

confidence: 57%

“…16,17 Moreover, T-cell protein tyrosine phosphatase (TCPTP) expression increases in the early stages of the disease, and pancreatic TCPTP deficiency mitigates cerulein-induced AP in mice. 18 These studies implicate PTPs in AP, but additional investigation into the contribution of these enzymes to disease pathogenesis is warranted.…”

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confidence: 99%

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

Bettaieb

Koike

Chahed

et al. 2016

The American Journal of Pathology

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Acute pancreatitis (AP) is a common and devastating gastrointestinal disorder that causes significant morbidity. The disease starts as local inflammation in the pancreas that may progress to systemic inflammation and complications. Protein tyrosine phosphatase 1B (PTP1B) is implicated in inflammatory signaling, but its significance in AP remains unclear. To investigate whether PTP1B may have a role in AP, we used pancreas PTP1B knockout (panc-PTP1B KO) mice and determined the effects of pancreatic PTP1B deficiency on cerulein-and arginine-induced acute pancreatitis. We report that PTP1B protein expression was increased in the early phase of AP in mice and rats. In addition, histological analyses of pancreas samples revealed enhanced features of AP in cerulein-treated panc-PTP1B KO mice compared with controls. Moreover, cerulein-and arginine-induced serum amylase and lipase were significantly higher in panc-PTP1B KO mice compared with controls. Similarly, pancreatic mRNA and serum concentrations of the inflammatory cytokines IL-1B, IL-6, and tumor necrosis factor-a were increased in panc-PTP1B KO mice compared with controls. Furthermore, panc-PTP1B KO mice exhibited enhanced cerulein-and arginine-induced NF-kB inflammatory response accompanied with increased mitogen-activated protein kinases activation and elevated endoplasmic reticulum stress. Notably, these effects were recapitulated in acinar cells treated with a pharmacological inhibitor of PTP1B. These findings reveal a novel role for pancreatic PTP1B in cerulein-and arginine-induced acute pancreatitis. (Am J Pathol 2016 http://dx

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“…In a study suggestive of a new target for pancreatitis treatment, T-cell protein tyrosine phosphatase (TCPTP) is found to be induced in acinar cells during acute pancreatitis [23]. Genetic ablation of TCPTP reduced the severity of acute pancreatitis as measured by serum levels of digestive enzymes.…”

Section: Er Stress and Autophagymentioning

confidence: 99%

The conspiracy of autophagy, stress and inflammation in acute pancreatitis

Hall

Crawford

2014

Current Opinion in Gastroenterology

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Purpose of review Acute pancreatitis (AP) is associated with alcohol abuse, gallstones and bacterial infection. Its basic etiology is tissue destruction accompanied by an innate inflammatory response, which induces epithelial stress pathways. Recent studies have focused on some of the integral cellular pathways shared between multiple pancreatitis models that also suggest new approaches to detection and treatment. Recent findings Several models of pancreatitis have been associated with stress responses, such as endoplasmic reticulum (ER) and oxidative stress together with the induction of a defective autophagic pathway. Recent evidence reinforces the critical role of these cellular processes in pancreatitis. A member of the the Toll-Like Receptor family, TLR4, which is known to contribute to disease pathology in many models of experimental pancreatitis, has been found to be a promising target for treatment of pancreatitis. Interestingly, a direct activator of TLR4,, the bacterial cell wall component in Gram negative bacteria lipopolysaccharide (LPS), contributes to the onset and severity of disease when combined with additional stressors, such as chronic alcohol feeding, however recent studies have shown that acute infection of mice with live bacteria is alone sufficient to induce acute pancreatitis. Summary In the last several months, the convergent roles of acinar cell stress, autophagy and proinflammatory signaling initiated by the toll-like receptors have been emphatically reinforced in the onset of acute pancreatitis.

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Pancreatic T cell protein-tyrosine phosphatase deficiency ameliorates cerulein-induced acute pancreatitis

Cited by 11 publications

References 74 publications

Pancreatic T cell protein–tyrosine phosphatase deficiency affects beta cell function in mice

Pancreatic T cell protein–tyrosine phosphatase deficiency affects beta cell function in mice

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

The conspiracy of autophagy, stress and inflammation in acute pancreatitis

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