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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 regulates cerulein-induced STAT3 and MAPKs signaling. Total pancreas lysates from control without (n = 9) and with (n = 12) cerulein and panc-TCPTP KO without (n = 7) and with (n = 9) cerulein were immunoblotted for pSTAT3, pERK1/2, pp38, pJNK1/2 and their respective unphosphorylated proteins, and Tubulin as a loading control. Bar graphs represent normalized data for pSTAT3/STAT3, pERK/ERK, pp38/p38, and pJNK/JNK, and presented as means ± SEM. (**: P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (#: P ≤ 0.05; ##: P ≤ 0.01) indicates significant difference between WT and KO mice.
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Figure 3: Pancreatic TCPTP deficiency regulates cerulein-induced STAT3 and MAPKs signaling. Total pancreas lysates from control without (n = 9) and with (n = 12) cerulein and panc-TCPTP KO without (n = 7) and with (n = 9) cerulein were immunoblotted for pSTAT3, pERK1/2, pp38, pJNK1/2 and their respective unphosphorylated proteins, and Tubulin as a loading control. Bar graphs represent normalized data for pSTAT3/STAT3, pERK/ERK, pp38/p38, and pJNK/JNK, and presented as means ± SEM. (**: P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (#: P ≤ 0.05; ##: P ≤ 0.01) indicates significant difference between WT and KO mice.

Mentions: To investigate the molecular basis for decreased AP in panc-TCPTP KO mice, we initially determined tyrosyl phosphorylation status of STAT3, a bona fide TCPTP substrate [18,26,29,30]. It is noteworthy that ablation of pancreatic STAT3 exacerbates cerulein-induced pancreatitis and demonstrates a protective effect of STAT3 against pancreatitis [45]. STAT3 is activated by phosphorylation at Tyr705 leading to dimerization and relocation to the nucleus to promote gene expression [46]. Immunoblots of total pancreatic lysates revealed significantly increased cerulein-induced STAT3 Tyr705 phosphorylation in panc-TCPTP KO mice compared with controls (Figure 3). Mitogen-activated protein kinases (MAPKs) including ERK1/2, p38 and JNK1/2 are induced rapidly and transiently during experimental AP in rodents [47]. This activation is believed to be a component of the cellular stress response in the onset of inflammation in the pancreas. Indeed, cerulein administration led to increased phosphorylation of ERK1/2, p38 and JNK in control mice that was significantly lower in panc-TCPTP KO mice (Figure 3). The decreased MAPK activation is in keeping with the reduced cerulein-induced AP and inflammation in panc-TCPTP KO mice. These findings demonstrate increased STAT3 phosphorylation and decreased MAPKs activation in pancreata of cerulein-treated panc-TCPTP KO mice.


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 regulates cerulein-induced STAT3 and MAPKs signaling. Total pancreas lysates from control without (n = 9) and with (n = 12) cerulein and panc-TCPTP KO without (n = 7) and with (n = 9) cerulein were immunoblotted for pSTAT3, pERK1/2, pp38, pJNK1/2 and their respective unphosphorylated proteins, and Tubulin as a loading control. Bar graphs represent normalized data for pSTAT3/STAT3, pERK/ERK, pp38/p38, and pJNK/JNK, and presented as means ± SEM. (**: P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (#: P ≤ 0.05; ##: 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 3: Pancreatic TCPTP deficiency regulates cerulein-induced STAT3 and MAPKs signaling. Total pancreas lysates from control without (n = 9) and with (n = 12) cerulein and panc-TCPTP KO without (n = 7) and with (n = 9) cerulein were immunoblotted for pSTAT3, pERK1/2, pp38, pJNK1/2 and their respective unphosphorylated proteins, and Tubulin as a loading control. Bar graphs represent normalized data for pSTAT3/STAT3, pERK/ERK, pp38/p38, and pJNK/JNK, and presented as means ± SEM. (**: P ≤ 0.01) indicates significant difference between saline- and cerulein-injected mice, and (#: P ≤ 0.05; ##: P ≤ 0.01) indicates significant difference between WT and KO mice.
Mentions: To investigate the molecular basis for decreased AP in panc-TCPTP KO mice, we initially determined tyrosyl phosphorylation status of STAT3, a bona fide TCPTP substrate [18,26,29,30]. It is noteworthy that ablation of pancreatic STAT3 exacerbates cerulein-induced pancreatitis and demonstrates a protective effect of STAT3 against pancreatitis [45]. STAT3 is activated by phosphorylation at Tyr705 leading to dimerization and relocation to the nucleus to promote gene expression [46]. Immunoblots of total pancreatic lysates revealed significantly increased cerulein-induced STAT3 Tyr705 phosphorylation in panc-TCPTP KO mice compared with controls (Figure 3). Mitogen-activated protein kinases (MAPKs) including ERK1/2, p38 and JNK1/2 are induced rapidly and transiently during experimental AP in rodents [47]. This activation is believed to be a component of the cellular stress response in the onset of inflammation in the pancreas. Indeed, cerulein administration led to increased phosphorylation of ERK1/2, p38 and JNK in control mice that was significantly lower in panc-TCPTP KO mice (Figure 3). The decreased MAPK activation is in keeping with the reduced cerulein-induced AP and inflammation in panc-TCPTP KO mice. These findings demonstrate increased STAT3 phosphorylation and decreased MAPKs activation in pancreata of cerulein-treated panc-TCPTP KO mice.

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