Enteral arginine modulates inhibition of AP-1/c-Jun by SP600125 in the postischemic gut.
We previously demonstrated that enteral arginine increased c-Jun/activator protein-1 (AP-1) DNA-binding activity and iNOS expression in a rodent model of mesenteric ischemia/reperfusion (I/R). The objective of this study was to specifically investigate the role of AP-1 in arginine's deleterious effect on the postischemic gut. We hypothesized that AP-1 inhibition would mitigate the effects of arginine. Using a rodent model of mesenteric I/R we demonstrated that gut neutrophil infiltration, activity of c-Jun/AP-1, as well as iNOS expression were increased by I/R and further increased by arginine while lessened by inhibition of c-Jun using the pharmacologic c-Jun N-terminal kinase inhibitor, SP600125. Similar results were demonstrated using a cell culture model of oxidant stress in IEC-6 cells. Importantly, effects of SP600125 were comparable to those of c-Jun silencing. Lastly, the specific iNOS inhibitor, 1400W, had no effect on either AP-1 or c-Jun. In conclusion, SP600125 attenuated the activity of c-Jun/AP-1, iNOS expression, and neutrophil infiltration induced by arginine following mesenteric I/R. Our data suggest that AP-1 inhibition mitigates the injurious inflammatory effects of arginine in the postischemic gut. Further investigation into the pathologic role of enteral arginine in the postischemic gut is warranted.
Department of Surgery, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 4.284, Houston, TX 77030, USA.
Kechen
K
Ban
Rachel
R
Santora
Rosemary A
RA
Kozar
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D001120:Arginine / Q000008:administration & dosage* / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004750:Enteral Nutrition; D020868:Gene Silencing / Q000187:drug effects; D007249:Inflammation; D007421:Intestine, Small / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000578:Amidines; D000873:Anthracenes; D001596:Benzylamines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; C432165:pyrazolanthrone; D004247:DNA; D001120:Arginine; D052247:Nitric Oxide Synthase Type II