In vitro evidence for role of ERK, p38, and JNK in exocrine pancreatic cytokine production.
Elucidation of mechanisms of acinar cell cytokine production is essential for a better understanding of acute pancreatitis pathogenesis. We hypothesize that the stress kinases ERK, p38, and JNK play an important role in acinar cell cytokine production. Rat pancreatic fragments were incubated with 100 nM concentration of the cholecystokinin analog caerulein or 100 nM caerulein and specific ERK inhibitor (100 microM PD98059), specific p38 inhibitor (10 microM SB203580), or specific JNK inhibitor (20 microM SP600125). After 3 hours of caerulein treatment, pancreatic fragments were homogenized and assayed for total and phosphorylated ERK, p38, and JNK, and for tumor necrosis factor-alpha or interleukin-1beta concentrations (ELISA). Pancreatic fragments stimulated with caerulein showed activation of ERK, p38, and JNK and increased cytokine concentrations (ANOVA, P<0.05). Specific stress kinase inhibitors significantly attenuated caerulein-induced activation of the corresponding stress kinase and cytokine production; however, the effect of the JNK inhibitor was comparatively less convincing. Increased activation of ERK, p38, and JNK in pancreatic fragments was not associated with significant increases in total ERK, total p38, or total JNK concentrations. The stress kinases ERK and p38 play an important role in caerulein-stimulated exocrine pancreatic overproduction of cytokines. The role of JNK needs further evaluation in this experimental model.
Samuel
Isaac
I
Department of Surgery, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, and Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Isaac-samuel@uiowa.edu
Zaheer
Asgar
A
Fisher
Rory A
RA
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002108:Ceruletide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D046790:Pancreas, Exocrine / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000873:Anthracenes; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D002108:Ceruletide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one