Mechanisms of dexamethasone-mediated chemokine down-regulation in mild and severe acute pancreatitis.
This study aimed to investigate the role of therapeutic dexamethasone (Dex) treatment on the mechanisms underlying chemokine expression during mild and severe acute pancreatitis (AP) experimentally induced in rats. Regardless of the AP severity, Dex (1 mg/kg), administered 1 h after AP, reduced the acinar cell activation of extracellular signal-regulated kinase (ERK) and c-Jun-NH(2)-terminal kinase (JNK) but failed to reduce p38-mitogen-activated protein kinase (MAPK) in severe AP. In both AP models, Dex inhibited the activation of nuclear factor-kappaB (NF-kappaB) and signal transducers and activators of transcription (STAT) factors. All of this resulted in pancreatic down-regulation of the chemokines monocyte chemoattractant protein-1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC). Lower plasma chemokine levels as well as decreased amylasemia, hematocrit and plasma interleukin-1beta (Il-1beta) levels were found either in mild or severe AP treated with Dex. Pancreatic neutrophil infiltration was attenuated by Dex in mild but not in severe AP. In conclusion, by targeting MAPKs, NF-kappaB and STAT3 pathways, Dex treatment down-regulated the chemokine expression in different cell sources during mild and severe AP, resulting in decreased severity of the disease.
Yubero
S
S
Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain.
Ramudo
L
L
Manso
M A
MA
De Dios
I
I
D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010195:Pancreatitis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D016328:NF-kappa B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases