Modulation in the expression of SHP-1, SHP-2 and PTP1B due to the inhibition of MAPKs, cAMP and neutrophils early on in the development of cerulein-induced acute pancreatitis in rats

Abstract

The protein tyrosine phosphatases (PTPs) SHP-1, SHP-2 and PTP1B are overexpressed early on during the development of cerulein -induced acute pancreatitis (AP) in rats, and their levels can be modulated by some species of mitogen-activated protein kinases (MAPKs), the intracellular levels of cAMP and by general leukocyte infiltration, the latter at least for SHP-2 and PTP1B. In this study we show that cerulein treatment activates extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) but not p38 MAPK during the early phase of cerulein-induced AP (2h after the first injection of cerulein). Therefore, by using the MAPK inhibitors SP600125 (a specific JNK inhibitor) and PD98059 (a specific ERK inhibitor), we have unmasked the particular MAPK that underlies the modulation of the expression levels of these PTPs. JNK would act by preventing SHP-1 protein expression from increasing beyond a certain level. ERK 1/2 was the main MAPK involved in the increase in SHP-2 protein expression due to cerulein. JNK negatively modulated the SH2-domain containing PTPs. Both MAPKs played a role in the increase in PTP1B protein expression due to cerulein. Finally, by using the white blood cell inhibitors vinblastine sulfate, gadolinium chloride and FK506 (tacrolimus), we show that the macrophage activity or T-lymphocytes does not modulate the expression of any of the PTPs, although neutrophil infiltration was found to be a regulator of SHP-2 and PTP1B protein expression due to cerulein.

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

“…60,61 PTP1B is induced by inflammation in vivo, and TNF-a treatment leads to increase in PTP1B mRNA and protein in insulin-and leptinresponsive tissues in mice, whereas TNF-a deficiency blocks diet-induced increase in expression. 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.…”

“…In addition, JNK and ERK have been implicated in the up-regulation of PTP1B expression on cerulein treatment. 16 Under basal conditions, MAPK activation was comparable between control and panc-PTP1B KO mice (Figure 4). However, cerulein and arginine administration led to increased phosphorylation of ERK1/2, p38, and JNK in control mice, and that was significantly higher in panc-PTP1B KO mice.…”

“…66 Of note, studies using MAPK pharmacological inhibitors suggest that JNK and ERK regulate cerulein-induced PTP1B expression. 16 The mechanism by which PTP1B deficiency potentiates MAPK signaling remains unknown, but can be indirect and related to increased inflammation. Last, ER stress is implicated in the pathophysiology of pancreatitis, 53,67 and attenuation of ER stress by chemical chaperones mitigates the disease in animal models.…”

“…Cerulein-induced AP is associated with increased expression of the SH2 domaincontaining phosphatases SHP1 and SHP2. 15,16 In addition, protein tyrosine phosphatase 1B (PTP1B) expression increases during the early stages of cerulein-induced AP and is suppressed by pharmacological inhibitors of mitogenactivated protein kinases (MAPKs). 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.…”

“…15,16 In addition, protein tyrosine phosphatase 1B (PTP1B) expression increases during the early stages of cerulein-induced AP and is suppressed by pharmacological inhibitors of mitogenactivated protein kinases (MAPKs). 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.…”