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

Bettaieb A, Xi Y, Hosein E, Coggins N, Bachaalany S, Wiede F, Perez S, Griffey SM, Sastre J, Tiganis T, Haj FG - Cell Commun. Signal (2014)

Bottom Line: T-cell protein tyrosine phosphatase (TCPTP) is implicated in inflammatory signaling but its significance in AP remains unclear.Amylase and lipase levels were lower in cerulein-treated panc-TCPTP KO mice compared with controls.These findings revealed a novel role for pancreatic TCPTP in the progression of cerulein-induced AP.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Nutrition, University of California Davis, One Shields Ave, 3135 Meyer Hall, Davis, CA 95616, USA. fghaj@ucdavis.edu.

ABSTRACT

Background: Acute pancreatitis (AP) is a common clinical problem whose incidence has been progressively increasing in recent years. Onset of the disease is trigged by intra-acinar cell activation of digestive enzyme zymogens that induce autodigestion, release of pro-inflammatory cytokines and acinar cell injury. T-cell protein tyrosine phosphatase (TCPTP) is implicated in inflammatory signaling but its significance in AP remains unclear.

Results: In this study we assessed the role of pancreatic TCPTP in cerulein-induced AP. TCPTP expression was increased at the protein and messenger RNA levels in the early phase of AP in mice and rats. To directly determine whether TCPTP may have a causal role in AP we generated mice with pancreatic TCPTP deletion (panc-TCPTP KO) by crossing TCPTP floxed mice with Pdx1-Cre transgenic mice. Amylase and lipase levels were lower in cerulein-treated panc-TCPTP KO mice compared with controls. In addition, pancreatic mRNA and serum concentrations of the inflammatory cytokines TNFα and IL-6 were lower in panc-TCPTP KO mice. At the molecular level, panc-TCPTP KO mice exhibited enhanced cerulein-induced STAT3 Tyr705 phosphorylation accompanied by a decreased cerulein-induced NF-κB inflammatory response, and decreased ER stress and cell death.

Conclusion: These findings revealed a novel role for pancreatic TCPTP in the progression of cerulein-induced AP.

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Related in: MedlinePlus

Pancreatic TCPTP deficiency decreases cerulein-induced pancreatic injury. A) Total pancreas lysates from wild type (WT) and panc-TCPTP KO (KO) mice were immunoblotted for TCPTP and Tubulin. B) Acute pancreatitis was induced by intraperitoneal injections of cerulein as detailed in Methods. Serum amylase and lipase were determined in control mice without (n = 9) and with (n = 12) cerulein and in panc-TCPTP KO mice without (n = 7) and with (n = 9) cerulein. C)TNFα, IL-6 and IL-1β expression (as assessed by quantitative real time PCR) in the pancreata of control mice without (n = 6) and with (n = 6) cerulein and panc-TCPTP KO mice without (n = 5) and with (n = 5) cerulein. D) Circulating levels of TNFα and IL-6 in serum of control mice without (n = 6) and with (n = 12) cerulein and panc-TCPTP KO mice without (n = 6) and with (n = 6) cerulein. (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (##; P ≤ 0.01) indicates significant difference between WT and KO mice.
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Figure 2: Pancreatic TCPTP deficiency decreases cerulein-induced pancreatic injury. A) Total pancreas lysates from wild type (WT) and panc-TCPTP KO (KO) mice were immunoblotted for TCPTP and Tubulin. B) Acute pancreatitis was induced by intraperitoneal injections of cerulein as detailed in Methods. Serum amylase and lipase were determined in control mice without (n = 9) and with (n = 12) cerulein and in panc-TCPTP KO mice without (n = 7) and with (n = 9) cerulein. C)TNFα, IL-6 and IL-1β expression (as assessed by quantitative real time PCR) in the pancreata of control mice without (n = 6) and with (n = 6) cerulein and panc-TCPTP KO mice without (n = 5) and with (n = 5) cerulein. D) Circulating levels of TNFα and IL-6 in serum of control mice without (n = 6) and with (n = 12) cerulein and panc-TCPTP KO mice without (n = 6) and with (n = 6) cerulein. (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (##; P ≤ 0.01) indicates significant difference between WT and KO mice.

Mentions: The increased expression of TCPTP upon cerulein administration prompted us to investigate the role of this phosphatase in AP. To that end, we crossed TCPTPfl/fl mice to those expressing Cre recombinase under the control of pancreatic and duodenal homeobox 1 (Pdx1) promoter to generate mice lacking TCPTP in the (endocrine and exocrine) pancreas [41]. Pancreatic TCPTP knockout mice (hereafter referred to as panc-TCPTP KO) survived to adulthood and did not display gross defects in pancreatic development. Immunoblot analysis of total pancreas lysates demonstrated significant reduction in TCPTP expression in panc-TCPTP KO mice compared with controls (Figure 2A). In addition, TCPTP expression was unchanged in other tissues such as hypothalamus, liver, muscle and adipose tissue (data not shown, and Xi et al., submitted). Similar to wild type mice, panc-TCPTP KO mice exhibited increased expression of SHP1 and PTP1B upon cerulein administration (Additional file 1: Figure S1). Thus, this mouse model provides efficient TCPTP deletion in the pancreas enabling the determination of TCPTP contribution to pancreatitis.


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

Bettaieb A, Xi Y, Hosein E, Coggins N, Bachaalany S, Wiede F, Perez S, Griffey SM, Sastre J, Tiganis T, Haj FG - Cell Commun. Signal (2014)

Pancreatic TCPTP deficiency decreases cerulein-induced pancreatic injury. A) Total pancreas lysates from wild type (WT) and panc-TCPTP KO (KO) mice were immunoblotted for TCPTP and Tubulin. B) Acute pancreatitis was induced by intraperitoneal injections of cerulein as detailed in Methods. Serum amylase and lipase were determined in control mice without (n = 9) and with (n = 12) cerulein and in panc-TCPTP KO mice without (n = 7) and with (n = 9) cerulein. C)TNFα, IL-6 and IL-1β expression (as assessed by quantitative real time PCR) in the pancreata of control mice without (n = 6) and with (n = 6) cerulein and panc-TCPTP KO mice without (n = 5) and with (n = 5) cerulein. D) Circulating levels of TNFα and IL-6 in serum of control mice without (n = 6) and with (n = 12) cerulein and panc-TCPTP KO mice without (n = 6) and with (n = 6) cerulein. (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (##; P ≤ 0.01) indicates significant difference between WT and KO mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016516&req=5

Figure 2: Pancreatic TCPTP deficiency decreases cerulein-induced pancreatic injury. A) Total pancreas lysates from wild type (WT) and panc-TCPTP KO (KO) mice were immunoblotted for TCPTP and Tubulin. B) Acute pancreatitis was induced by intraperitoneal injections of cerulein as detailed in Methods. Serum amylase and lipase were determined in control mice without (n = 9) and with (n = 12) cerulein and in panc-TCPTP KO mice without (n = 7) and with (n = 9) cerulein. C)TNFα, IL-6 and IL-1β expression (as assessed by quantitative real time PCR) in the pancreata of control mice without (n = 6) and with (n = 6) cerulein and panc-TCPTP KO mice without (n = 5) and with (n = 5) cerulein. D) Circulating levels of TNFα and IL-6 in serum of control mice without (n = 6) and with (n = 12) cerulein and panc-TCPTP KO mice without (n = 6) and with (n = 6) cerulein. (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (##; P ≤ 0.01) indicates significant difference between WT and KO mice.
Mentions: The increased expression of TCPTP upon cerulein administration prompted us to investigate the role of this phosphatase in AP. To that end, we crossed TCPTPfl/fl mice to those expressing Cre recombinase under the control of pancreatic and duodenal homeobox 1 (Pdx1) promoter to generate mice lacking TCPTP in the (endocrine and exocrine) pancreas [41]. Pancreatic TCPTP knockout mice (hereafter referred to as panc-TCPTP KO) survived to adulthood and did not display gross defects in pancreatic development. Immunoblot analysis of total pancreas lysates demonstrated significant reduction in TCPTP expression in panc-TCPTP KO mice compared with controls (Figure 2A). In addition, TCPTP expression was unchanged in other tissues such as hypothalamus, liver, muscle and adipose tissue (data not shown, and Xi et al., submitted). Similar to wild type mice, panc-TCPTP KO mice exhibited increased expression of SHP1 and PTP1B upon cerulein administration (Additional file 1: Figure S1). Thus, this mouse model provides efficient TCPTP deletion in the pancreas enabling the determination of TCPTP contribution to pancreatitis.

Bottom Line: T-cell protein tyrosine phosphatase (TCPTP) is implicated in inflammatory signaling but its significance in AP remains unclear.Amylase and lipase levels were lower in cerulein-treated panc-TCPTP KO mice compared with controls.These findings revealed a novel role for pancreatic TCPTP in the progression of cerulein-induced AP.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Nutrition, University of California Davis, One Shields Ave, 3135 Meyer Hall, Davis, CA 95616, USA. fghaj@ucdavis.edu.

ABSTRACT

Background: Acute pancreatitis (AP) is a common clinical problem whose incidence has been progressively increasing in recent years. Onset of the disease is trigged by intra-acinar cell activation of digestive enzyme zymogens that induce autodigestion, release of pro-inflammatory cytokines and acinar cell injury. T-cell protein tyrosine phosphatase (TCPTP) is implicated in inflammatory signaling but its significance in AP remains unclear.

Results: In this study we assessed the role of pancreatic TCPTP in cerulein-induced AP. TCPTP expression was increased at the protein and messenger RNA levels in the early phase of AP in mice and rats. To directly determine whether TCPTP may have a causal role in AP we generated mice with pancreatic TCPTP deletion (panc-TCPTP KO) by crossing TCPTP floxed mice with Pdx1-Cre transgenic mice. Amylase and lipase levels were lower in cerulein-treated panc-TCPTP KO mice compared with controls. In addition, pancreatic mRNA and serum concentrations of the inflammatory cytokines TNFα and IL-6 were lower in panc-TCPTP KO mice. At the molecular level, panc-TCPTP KO mice exhibited enhanced cerulein-induced STAT3 Tyr705 phosphorylation accompanied by a decreased cerulein-induced NF-κB inflammatory response, and decreased ER stress and cell death.

Conclusion: These findings revealed a novel role for pancreatic TCPTP in the progression of cerulein-induced AP.

Show MeSH
Related in: MedlinePlus