Imbalance between pro-inflammatory and anti-inflammatory mediators in the rat ileal mucosa after irradiation: Pivotal role of PPARs
C. Linard, O.Gremy, M. Benderitter, 4th European mucosal immunilogy group meeting, 8-10/10/2004, Lyon.
Because irradiation can cause acute enteritis that leads to reduced motility and in a later phase to fibrosis, the small bowel is an important dose-limiting organ following radiotherapy. Pathologic changes may be caused by the early stage of an inflammatory process; we therefore studied the irradiation effect on the imbalance between pro and anti-inflammatory and events on the rat ileal mucosa. Analyses by real-time-PCR show that whole body 10G-g irradiation induced an increase of TNF-a and IL-6 expression at 6h and persisting at 3 days post-irradiation in the ileal mucosa. IFN-g was significantly elevated (2.4-fold; p<0.01) at 3 days. In opposite, the anti-inflammatory cytokine IL-10 mRNA was markedly lower as early as 6h post-irradiation. Analysis of PPARs implicated in the anti-inflammatory and anti-apoptotic events show a drastic decrease of the mRNA levels for PPARa (80%) correlates with a heterodimer RXR alteration at 3 days. PPARs have the ability to inhibit CINC and MCP-1. PPARs repression contributes to overexpressions of MCP-1 and CINC with a 6-fold (p<0.005) and 20-fold (p<0.01) increase respectively. CINC increase with was accompanied by increased expression of ICAM-1 (2.4-fold) contributed to the recruitment of MPO-positive cells in the mucosa at 3 days. Interestingly, pro-apoptotic gene Bax expression remained unaffected at 3 days post-irradiation. In conclusion, irradiation induced an an early (but lasting up to 3 days) imbalance between pro-inflammatory (TNF-a, IL-6, IFN-g, CINC, MCP-1) and anti-inflammatory (PPARa, IL-10) mediators contributed to an ileal mucosa, infiltration of inflammatory cells. A therapeutic strategy targeting PPARs may counterbalance the radiation-induced inflammatory process.