Received for publication July 24, 2007.
Revised December 11, 2007.
Accepted for publication December 11, 2007.

Reduction of PPAR expression by -irradiation as a mechanism contributing to inflammatory response in rat colon: Modulation by the 5-ASA agonist

Abstract

Radiation-induced intestinal injuries, including inflammation and immune response, remain a limiting factor in the effectiveness of pelvic radiotherapy and in the patient's quality of life during and after treatment. Peroxisome proliferation-activated receptor (PPAR) agonists are now emerging as therapeutic drugs for various inflammatory diseases that are characterized by impaired PPAR expression. The purpose of this study was to investigate the profile of PPAR expression in rat colonic mucosa 3 and 7 days after abdominal -irradiation (10 Gy). We tested whether irradiation-induced acute inflammatory response could be modulated pharmacologically with the anti-inflammatory properties of 5-aminosalicylic acid (5-ASA) (250 mg/kg/day), which is a PPAR activator. Irradiation drastically reduced mRNA and protein levels of PPAR and - and of the heterodimer RXR at 3 days post-irradiation. 5-ASA treatment normalized both PPAR and RXR expression at 3 days post-irradiation and PPAR at 7 days. By promoting PPAR expression and its nuclear translocation, 5-ASA interfered with the NF-B pathway, both by reducing irradiation-induced NF-B p65 translocation and increasing the expression of IB inhibitor mRNA and protein. 5-ASA therefore prevents irradiation-induced inflammatory processes as well as expression of TNF, MCP-1, iNOS and macrophage infiltration. In addition, 5-ASA restores the IFN/STAT-1 and STAT-3 concentrations that were impaired at 3 and 7 days post-irradiation and which are correlated with SOCS-3 repression. Collectively, these results indicate that PPAR agonists may be effective in the prevention of inflammatory processes and immune responses during and after pelvic radiotherapy.

Key words: Inflammation, Intestine, Irradiation, NF-kB, PPAR, STAT