Elsevier

Translational Research

Volume 160, Issue 2, August 2012, Pages 153-161
Translational Research

Original Article
Pioglitazone, a PPAR-γ activator, attenuates the severity of cerulein-induced acute pancreatitis by modulating early growth response-1 transcription factor

https://doi.org/10.1016/j.trsl.2012.02.003Get rights and content

The purpose of this study was to test the hypothesis that activation of endogenous peroxisome proliferator-activated receptor (PPARγ) inhibits induction of early growth response factor-1 (Egr-1), which is rapidly induced in the pancreas following cerulein intraperitoneal injection. Acute pancreatitis was induced in mice by hourly intraperitoneal injection of cerulein. Pioglitazone was administered prophylactically and pancreatic inflammation was assessed. AR42J cells were stimulated with caerulein10−8M co-incubated in presence of different concentration of pioglitazone. The expression of PPARγ, Egr-1, and the target genes of Egr-1 were studied by real-time reverse transcriptase polymerase chain reaction (PCR), Western blot, and immunohistochemistry. In vitro, a PPAR-γ activator (pioglitazone) strikingly diminished Egr-1 mRNA and protein expression corresponding to Egr-1. In vivo, treatment with pioglitazone prior to the intraperitoneal injection of cerulein induction of Egr-1 and its target genes such as, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). The inhibitory effect of pioglitazone on Egr-1 expression induced by cerulein was almost fully restored by GW9662. Activation of PPAR-γ suppressed the activation of Egr-1 and its inflammatory gene targets and provided potent protection against pancreas injury. These data suggest a new mechanism in which PPAR-γ activation may decrease tissue inflammation in response to a cerulein insult.

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Cell culture

The first set of experiments was designed to determine if PPAR-γ activators could inhibit the increased expression of Egr-1 observed in AR42J cells. Rat pancreatic acinar AR42J cells were obtained from the American Type Culture Collection and cultured in Dulbecco’s modified Eagle’s medium (DMEM, Sigma, St Louis, Mo) supplemented with 10% fetal bovine serum and antibiotics (100 U/mL penicillin and 100 mg/mL streptomycin) with 44 mM sodium bicarbonate and 10% CO2 as recommended.9 The acinar cells

Effects of PPAR-γ activators on Egr-1 expression and activity in cerulein-treated AR42J cells

Egr-1 mRNA levels measured by real-time RT- PCR 30 min after treatment with cerulein were markedly elevated in the group of cells treated with DMSO alone as a control (Fig 1, A and B). In cells treated with 20 μM or 40 μM pioglitazone, but otherwise subjected to identical cerulein procedures, Egr-1 mRNA levels were significantly reduced (P < 0.05).

Concordant with these observations, analyses of the expression of Egr-1 protein showed that pioglitazone significantly inhibited increased levels of

Discussion

Acute pancreatitis involves several separate processes, including acinar cell damage, thrombosis, increased vascular permeability, and local and systemic inflammation. These disease processes are initiated by pancreatic acinar cells in response to stress. To date, the mechanisms mediating these events are not well understood. Many acinar cell responses, especially the most rapid, include the activation of proteins by post-translational modifications, including stress kinases,12 trypsinogen,13

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