Reduction of peroxisome proliferation-activated receptor gamma expression by gamma-irradiation as a mechanism contributing to inflammatory response in rat colon: modulation by the 5-aminosalicylic acid agonist.
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 gamma-irradiation (10 Gy). We tested whether irradiation-induced acute inflammatory response could be modulated pharmacologically with the antiinflammatory properties of 5-aminosalicylic acid (5-ASA) (250 mg/kg/day), which is a PPAR activator. Irradiation drastically reduced mRNA and protein levels of PPARalpha and -gamma and of the heterodimer retinoid X receptor (RXR)alpha at 3 days postirradiation. 5-ASA treatment normalized both PPARgamma and RXRalpha expression at 3 days postirradiation and PPARalpha at 7 days. By promoting PPAR expression and its nuclear translocation, 5-ASA interfered with the nuclear factor (NF)-kappaB pathway, both by reducing irradiation-induced NF-kappaB p65 translocation/activation and increasing the expression of nuclear factor-kappaB inhibitor (IkappaB) mRNA and protein. Therefore, 5-ASA prevents irradiation-induced inflammatory processes as well as expression of tumor necrosis factor alpha, monocyte chemotactic protein-1, inducible nitric-oxide synthase, and macrophage infiltration. In addition, 5-ASA restores the interferon gamma/signal transducer and activator of transcription (STAT)-1 and STAT-3 concentrations that were impaired at 3 and 7 days postirradiation and are correlated with suppressor of cytokine signaling-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.
Linard
Christine
C
Institut de Radioprotection et de Sûreté Nucléaire, Direction de la Radioprotection de l'Homme, Laboratoire de Radiopathology, B.P. no. 17, F-92262 Fontenay-aux-Roses Cedex, France. christine.linard@irsn.fr
Grémy
Olivier
O
Benderitter
Marc
M
D000818:Animals; D003092:Colitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D019804:Mesalamine / Q000494:pharmacology* / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism / Q000528:radiation effects*; D051381:Rats; D017208:Rats, Wistar
D047495:PPAR gamma; D019804:Mesalamine