AIM: To investigate if an immune imbalance may ac-count for the development and progression of chronic radiation enteritis. We analyzed the Th1/Th2 immune response profile early and 6 mo after fractionated colorectal irradiation. METHODS: A rat model of fractionated colorectal γ-irradiation (4-Gy fractions, 3 fractions per week) was designed to investigate the effects of cumulative dose on inflammatory mediators (cytokines and chemo-k/nes) and immune response (Th1/Th2 profile and im-munosuppressive mediator It-10) during acute (early) response and 6 mo after the end of fractionated irradia-tion (chronic response). Analyses were performed 1 d after the cumulative doses of 16 Gy and 36 Gy and 1 d, 3 d, and 26 wk after the cumulative dose of 52 Gy. RESULTS: Without causing histological damage, frac-tionated radiation induced elevated expression of IL-1β,TNFα, MCP-1, and iNOS in distal colonic mucosa dur-ing the early post-irradiation phase. At that time, a Th2 profile was confirmed by expression of both the Th2-specific transcription factor GATA-3 and the chemokine receptor CCR4 and by suppression of the Th1 cytokine IFNγ/IP-10 throughout the irradiation protocol. After 6 too, despite the 2-fold reduction of iNOS and MCP-1 levels, the Th2 profile persisted, as shown by a 50% re-duction in the expression of the Th1 transcription factor T-bet, the chemokine receptor CCXCR3, and the IFNy/ STAT1 pathway. At the same time-point, the immuno-suppressive IL-10/STAT3 pathway, known to regulate the Th1/Th2 balance, was expressed, in irradiated rats, at approximately half its level as compared to controls. This suppression was associated with an overexpression of SOCS3, which inhibits the feedback of the Th1 polar-ization and regulates IL-10 production.CONCLUSION: Colorectal irradiation induces Th2 po-larization, defective IL-10/STAT3 pathway activation and sacs3 overexpression. These changes, in turn, main-rain a immunological imbalance that persists in the long term.