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.
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.
Department of Biochemistry and Molecular Biology, University of Salamanca, Spain.
Violeta
V
García-Hernández
Department of Biochemistry and Molecular Biology, University of Salamanca, Spain.
Nancy
N
Sarmiento
Department of Biochemistry and Molecular Biology, University of Salamanca, Spain.
Carmen
C
Sánchez-Bernal
Department of Biochemistry and Molecular Biology, University of Salamanca, Spain.
Laura
L
Matellán
Department of Physiology and Pharmacology, University of Salamanca, Spain.
José J
JJ
Calvo
Department of Biochemistry and Molecular Biology, University of Salamanca, Spain. Electronic address: sanyaj@usal.es.
Jesús
J
Sánchez-Yagüe
D000208:Acute Disease; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002108:Ceruletide; D000242:Cyclic AMP / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020556:Neutrophil Infiltration; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000873:Anthracenes; D005419:Flavonoids; C432165:pyrazolanthrone; D002108:Ceruletide; D000242:Cyclic AMP; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C516610:Ptpn1 protein, rat; C509250:Ptpn6 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Experimental acute pancreatitis; Infiltration inhibition; MAPK inhibition; PTP1B; SHP-1; SHP-2