Colorectal Cancer
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Dec 14, 2008; 14(46): 7075-7085
Published online Dec 14, 2008. doi: 10.3748/wjg.14.7075
Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation
Olivier Grémy, Marc Benderitter, Christine Linard
Olivier Grémy, Marc Benderitter, Christine Linard, Institute for Radioprotection and Nuclear safety, B.P. n°17, F-92262 Fontenay aux Roses Cedex, France
Author contributions: Grémy O and Linard C contributed equally to this work; Linard C designed research; Grémy O and Linard C performed research, analyzed data and wrote the paper; Benderitter M contributed to the scientific discussion.
Correspondence to: Christine Linard, Institute for Radioprotection and Nuclear safety, B.P. n°17, F-92262 Fontenay-aux-Roses Cedex, France.
Telephone: +33-1-58359186 Fax: +33-1-58358467
Received: July 29, 2008
Revised: November 14, 2008
Accepted: November 21, 2008
Published online: December 14, 2008

AIM: To investigate if an immune imbalance may account 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 chemokines) and immune response (Th1/Th2 profile and immunosuppressive mediator IL-10) during acute (early) response and 6 mo after the end of fractionated irradiation (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, fractionated radiation induced elevated expression of IL-1β, TNFα, MCP-1, and iNOS in distal colonic mucosa during 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 mo, despite the 2-fold reduction of iNOS and MCP-1 levels, the Th2 profile persisted, as shown by a 50% reduction in the expression of the Th1 transcription factor T-bet, the chemokine receptor CCXCR3, and the IFNγ/STAT1 pathway. At the same time-point, the immunosuppressive 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 polarization and regulates IL-10 production.

CONCLUSION: Colorectal irradiation induces Th2 polarization, defective IL-10/STAT3 pathway activation and SOCS3 overexpression. These changes, in turn, maintain a immunological imbalance that persists in the long term.

Keywords: Colorectum, Inflammation, Th2 cells, Irradiation, Suppressor of cytokine signaling 3, STAT