The proteasome inhibitor MG132 protects against acute pancreatitis.
The cell-permeant MG132 tripeptide (Z-Leu-Leu-Leu-aldehyde) is a peptide aldehyde proteasome inhibitor that also inhibits other proteases, including calpains and cathepsins. By blocking the proteasome, this tripeptide has been shown to induce the expression of cell-protective heat shock proteins (HSPs) in vitro. Effects of MG132 were studied in an in vivo model of acute pancreatitis. Pancreatitis was induced in male Wistar rats by injecting 2 x 100 microug/kg cholecystokinin octapeptide intraperitoneally (ip) at an interval of 1 h. Pretreating the animals with 10 mg/kg MG132 ip before the induction of pancreatitis significantly inhibited IkappaB degradation and subsequent activation of nuclear factor-kappaB (NF-kappaB). MG132 also increased HSP72 expression. Induction of HSP72 and inhibition of NF-kappaB improved parameters of acute pancreatitis. Thus MG132 significantly decreased serum amylase, pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, proinflammatory cytokine concentrations, and the expression of pancreatitis-associated protein. Parameters of oxidative stress (GSH, MDA, SOD, etc.) were improved in both the serum and the pancreas. Histopathological examinations revealed that pancreatic specimens of animals pretreated with the peptide demonstrated milder edema, cellular damage, and inflammatory activity. Our findings show that simultaneous inhibition of calpains, cathepsins, and the proteasome with MG132 prevents the onset of acute pancreatitis.
Letoha
Tamás
T
Department of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. tletoha@yahoo.com
Somlai
Csaba
C
Takács
Tamás
T
Szabolcs
Annamária
A
Rakonczay
Zoltán
Z
Jármay
Katalin
K
Szalontai
Tamás
T
Varga
Ilona
I
Kaszaki
József
J
Boros
Imre
I
Duda
Erno
E
Hackler
László
L
Kurucz
István
I
Penke
Botond
B
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D001835:Body Weight; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D007976:Leupeptins / Q000627:therapeutic use*; D008168:Lung / Q000201:enzymology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000073718:Pancreatitis-Associated Proteins; D061988:Proteasome Inhibitors; D051381:Rats; D017208:Rats, Wistar; D012844:Sincalide / Q000633:toxicity
D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D050884:HSP72 Heat-Shock Proteins; D007976:Leupeptins; D016328:NF-kappa B; D000073718:Pancreatitis-Associated Proteins; D061988:Proteasome Inhibitors; C000612141:REG3A protein, human; D000681:Amylases; D012844:Sincalide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde