The anti-inflammatory effect of methylprednisolone occurs down-stream of nuclear factor-kappaB DNA binding in acute pancreatitis.
Glucocorticoids are potent anti-inflammatory drugs. The molecular mechanisms underlying these effects have not yet been fully revealed. The aim of the present study was to establish whether methylprednisolone pretreatment is beneficial and if it can block the pancreatic DNA binding of the transcription factor nuclear factor-kappaB (NF-kappaB) and proinflammatory cytokine synthesis during cholecystokinin-octapeptide (CCK)-induced acute pancreatitis in rats. Additionally, we set out to investigate the potential effects of methylprednisolone and CCK on pancreatic heat shock protein (HSP) synthesis. The dose-response (5-40 mg/kg) and time-course (6-72 h) curves of methylprednisolone on pancreatic HSP60 and HSP72 synthesis were evaluated following methylprednisolone treatment. We demonstrated that methylprednisolone specifically and dose-dependently induced HSP72 in the pancreas of rats, while it did not have a significant effect on HSP60 expression. The pancreatitis was induced near the peak level of HSP72 synthesis (2 x 30 mg/kg body weight [b.w.] methylprednisolone i.m. at an interval of 12 h, followed by a 12-h recovery period after the second injection of methylprednisolone) by administering 2 x 100 microg/kg CCK subcutaneously at an interval of 1 h. The injections of CCK in the vehicle-pretreated group significantly elevated the levels of pancreatic HSP60 and HSP72 2-4 h after the second CCK injection. Methylprednisolone pretreatment ameliorated many of the examined laboratory (the pancreatic weight/body weight [p.w./b.w.] ratio, the serum amylase activity, the plasma trypsinogen activation peptide concentration, the pancreatic levels of tumor necrosis factor-alpha and interleukin-6, the degree of lipid peroxidation, protein oxidation, nonprotein sulfhydryl group content and the pancreatic myeloperoxidase activity) and morphological parameters of the disease. Methylprednisolone pretreatment did not influence pancreatic NF-kappaB DNA binding, but decreased proinflammatory cytokine synthesis in this acute pancreatitis model. The findings suggest that the anti-inflammatory effect of large doses of methylprednisolone in secretagogue-induced pancreatitis occurs downstream of NF-kappaB DNA binding, and that increased pancreatic HSP72 synthesis may play a role in the protective effect of the drug.
Rakonczay
Zoltán
Z
First Department of Medicine, University of Szeged, P.O. Box 469, Hungary. raz@in1st.szote.u-szeged.hu
Duda
Erno
E
Kaszaki
József
J
Iványi
Béla
B
Boros
Imre
I
Lonovics
János
J
Takács
Tamás
T
D000208:Acute Disease; D000681:Amylases / Q000097:blood / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D018834:Chaperonin 60 / Q000096:biosynthesis / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000187:drug effects; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009842:Oligopeptides / Q000097:blood / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012844:Sincalide / Q000008:administration & dosage; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D018834:Chaperonin 60; D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D008054:Lipid Peroxides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D009842:Oligopeptides; D011506:Proteins; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; C080396:trypsinogen activation peptide; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D009195:Peroxidase; D000681:Amylases; D012844:Sincalide; D008775:Methylprednisolone