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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

Increased TCPTP expression in acute pancreatitis. A) Total pancreas lysates of wild type mice that were administered saline (control; Ctr; n = 9) or cerulein (Cer; n = 12) immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. B)TCPTP, PTP1B and SHP1 expression as assessed by quantitative real time PCR in the pancreata of wild type mice without (-) (n = 6) and with (+) (n = 8) cerulein administration. For A and B (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice. C) Total pancreas lysates of rats that were administered saline or taurocholate, sacrificed after 1 and 6 h then immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. (**; P ≤ 0.01) indicates significant difference between saline- and taurocholate-injected rats.
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Figure 1: Increased TCPTP expression in acute pancreatitis. A) Total pancreas lysates of wild type mice that were administered saline (control; Ctr; n = 9) or cerulein (Cer; n = 12) immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. B)TCPTP, PTP1B and SHP1 expression as assessed by quantitative real time PCR in the pancreata of wild type mice without (-) (n = 6) and with (+) (n = 8) cerulein administration. For A and B (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice. C) Total pancreas lysates of rats that were administered saline or taurocholate, sacrificed after 1 and 6 h then immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. (**; P ≤ 0.01) indicates significant difference between saline- and taurocholate-injected rats.

Mentions: AP was induced by repetitive intraperitoneal injections of cerulein, an analog of the secretagogue cholecystokinin, to wild type mice and expression of TCPTP was determined. Immunoblots of pancreatic lysates demonstrated increased TCPTP expression upon cerulein administration (Figure 1A). Expression of the closely related PTP1B and the SH2 domain-containing phosphatase SHP1 was increased upon cerulein administration consistent with published reports [16,17]. In addition, mRNAs of the genes encoding TCPTP, PTP1B and SHP1, as determined by real time RT-PCR, were increased in the pancreas upon cerulein administration (Figure 1B). Similarly, pancreatic TCPTP, SHP1 and PTP1B protein expression was increased in a taurocholate-induced AP rat model [39,40] (Figure 1C). Together, these findings demonstrate that AP is associated with increases in TCPTP at the level of both mRNA and protein.


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)

Increased TCPTP expression in acute pancreatitis. A) Total pancreas lysates of wild type mice that were administered saline (control; Ctr; n = 9) or cerulein (Cer; n = 12) immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. B)TCPTP, PTP1B and SHP1 expression as assessed by quantitative real time PCR in the pancreata of wild type mice without (-) (n = 6) and with (+) (n = 8) cerulein administration. For A and B (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice. C) Total pancreas lysates of rats that were administered saline or taurocholate, sacrificed after 1 and 6 h then immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. (**; P ≤ 0.01) indicates significant difference between saline- and taurocholate-injected rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Increased TCPTP expression in acute pancreatitis. A) Total pancreas lysates of wild type mice that were administered saline (control; Ctr; n = 9) or cerulein (Cer; n = 12) immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. B)TCPTP, PTP1B and SHP1 expression as assessed by quantitative real time PCR in the pancreata of wild type mice without (-) (n = 6) and with (+) (n = 8) cerulein administration. For A and B (**; P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice. C) Total pancreas lysates of rats that were administered saline or taurocholate, sacrificed after 1 and 6 h then immunoblotted for TCPTP, PTP1B, SHP1 and Tubulin. Bar graph represents expression of TCPTP, PTP1B and SHP1 (normalized to Tubulin) and presented as means ± SEM. (**; P ≤ 0.01) indicates significant difference between saline- and taurocholate-injected rats.
Mentions: AP was induced by repetitive intraperitoneal injections of cerulein, an analog of the secretagogue cholecystokinin, to wild type mice and expression of TCPTP was determined. Immunoblots of pancreatic lysates demonstrated increased TCPTP expression upon cerulein administration (Figure 1A). Expression of the closely related PTP1B and the SH2 domain-containing phosphatase SHP1 was increased upon cerulein administration consistent with published reports [16,17]. In addition, mRNAs of the genes encoding TCPTP, PTP1B and SHP1, as determined by real time RT-PCR, were increased in the pancreas upon cerulein administration (Figure 1B). Similarly, pancreatic TCPTP, SHP1 and PTP1B protein expression was increased in a taurocholate-induced AP rat model [39,40] (Figure 1C). Together, these findings demonstrate that AP is associated with increases in TCPTP at the level of both mRNA and protein.

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