Abdominal irradiation increases inflammatory cytokine expression and activates NF-κB in rat ileal muscularis layer

Abstract

The small bowel is an important dose-limiting organ in abdominal radiotherapy because irradiation can cause acute enteritis that, in turn, leads to progressively reduced motility and finally, in a later phase, to fibrosis. Because these clinical symptoms may be caused by the early stage of an inflammatory process, we characterized the radiation-induced intestinal inflammation in rats. Abdominal gamma-irradiation (10-Gy) induced a cascade of inflammatory events characterized by an early (6 h after exposure) increase in IL-1beta, TNF-alpha, and IL-6 mRNA levels in the rat ileal muscularis layer. IL-8 [a cytokine-induced neutrophil chemoattractant (CINC)] mRNA appeared later (at 3 days). The expression of TGF-beta (a profibrotic cytokine) was higher in irradiated than control tissue at day 1, whereas IL-10 (an anti-inflammatory cytokine) expression vanished completely. Despite strong IL-1ra expression, the IL-1ra/IL-1beta ratio, which is an indicator of inflammatory balance, was -41% at day 1 in irradiated compared with control tissue. The nuclear transcription factors NF-kappaB and activator protein-1 (AP-1) govern transcription of these genes, directly or indirectly. Although expression of the subunits of NF-kappaB (p65, p50) and AP-1 (c-fos, c-jun) did not increase, irradiation caused a rapid and persistent translocation of p65 and p50. An imbalance between proinflammatory and anti-inflammatory mediators may contribute to perpetuating intestinal inflammation, thus making it chronic.

Effects of genistein following fractionated lung irradiation in mice

“…Transcription factors also play an important role in the progression of the inflammatory lung response following irradiation [71,95,96]. Nuclear factor kappa B (NF-κB) has been shown to be continuously activated following irradiation and is involved in initiating and sustaining the inflammatory response [97,98].…”

Reduction of Peroxisome Proliferation-Activated Receptor γ Expression by γ-Irradiation as a Mechanism Contributing to Inflammatory Response in Rat Colon: Modulation by the 5-Aminosalicylic Acid Agonist

“…These radiationinduced intestinal injuries thus continue to limit the effectiveness of radiotherapy (Andreyev, 2005). We previously reported that an inflammatory process induced by abdominal irradiation (Linard et al, 2003) is associated with an imbalance of the Th1/Th2 adaptive immune response that results in repression of genes involved in Th1 differentiation, cytokine responses (IFN␥) and migratory behavior (Grémy et al, 2006). Differentiation toward the Th2 pathway requires upregulation of endogenous feedback regulators such as suppressor of cytokine signaling (SOCS)-3 in several inflammatory models (Seki et al, 2003;Li et al, 2006), including abdominal irradiation (Grémy et al, 2006).…”

Contribution des atteintes gastro-intestinales dans le développement du syndrome de défaillance multi-viscérale radio-induit

“…Des modifications de la perméabilité vasculaire vis-à-vis des molécules et/ou de cellules jouent clairement un rôle fondamental dans la mise en place de la réponse inflammatoire. Pour conforter cette hypothèse, plusieurs études expérimentales rapportent une augmentation radio-induite de la libération de divers médiateurs (cytokines pro-inflammatoires, bio-amines, monoxyde d'azote) associée à une surexpression des molécules d'adhésion au niveau intestinal (Buell et Harding, 1989 ;Panès et al, 1995 ;Freeman et Mac Naughton, 2000 ;Linard et al, 2003). Ces arguments viennent renforcer l'idée avancée précédemment mettant en avant le rôle de l'hypoperfusion intestinale dans la libération massive de médiateurs inflammatoires : ceci pourrait avoir à la fois une incidence locale mais également sur des organes distants et viendrait illustrer le rôle clé que l'intestin peut jouer dans la mise en place du SDMV.…”