Glutamate cysteine ligase up-regulation fails in necrotizing pancreatitis.
Glutathione depletion is a key factor in the development of acute pancreatitis. Our aim was to study the regulation of glutamate cysteine ligase, the rate-limiting enzyme in glutathione synthesis, in edematous or necrotizing pancreatitis in rats. Glutathione levels were kept low in necrotizing pancreatitis for several hours, with no increase in protein or mRNA levels of glutamate cysteine ligase subunits, despite binding of RNA polymerase II to their promoters and coding regions. The survival signal pathway mediated by ERK and c-MYC was activated, and c-MYC was recruited to the promoters. The failure in gene up-regulation seems to be due to a marked increase in cytosolic ribonuclease activity. In contrast, in edematous pancreatitis glutathione levels were depleted and rapidly restored, and protein and mRNA expression of glutamate cysteine ligase increased markedly due to enhanced transcription mediated by recruitment of c-MYC, NF-kappaB, and SP-1 to the promoters. No increase in cytosolic ribonuclease activity was found in this case. We propose a novel pathophysiological mechanism to differentiate necrotizing from edematous pancreatitis, which is the inefficient up-regulation of glutamate cysteine ligase caused by increased cytosolic ribonuclease activity in the severe form of the disease. This mechanism would abrogate a rapid recovery of glutathione levels.
Pereda
Javier
J
Department of Physiology, University of Valencia, 46100 Burjasot (Valencia), Spain.
Escobar
Javier
J
Sandoval
Juan
J
Rodríguez
José Luis
JL
Sabater
Luis
L
Pallardó
Federico V
FV
Torres
Luis
L
Franco
Luis
L
Viña
José
J
López-Rodas
Gerardo
G
Sastre
Juan
J
D000818:Animals; D002108:Ceruletide; D004487:Edema / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis*; D005978:Glutathione / Q000172:deficiency; D008297:Male; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000201:enzymology*; D012319:RNA Polymerase II / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012260:Ribonucleases / Q000378:metabolism; D013656:Taurocholic Acid; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D014157:Transcription Factors; D013656:Taurocholic Acid; D002108:Ceruletide; D012319:RNA Polymerase II; D012260:Ribonucleases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione