Acute and persisting Th2-like immune response after fractionated colorectal gamma-irradiation.
OBJECTIVE
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 gamma-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-1beta, TNFalpha, 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 IFNgamma/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 IFNgamma/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.


CONCLUSIONS
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.
Gremy
Olivier
O
Institute for Radioprotection and Nuclear safety, F-92262 Fontenay-aux-Roses Cedex, France.
Benderitter
Marc
M
Linard
Christine
C
D000818:Animals; D003106:Colon / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D018928:Immunity, Mucosal / Q000528:radiation effects*; D016753:Interleukin-10 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D008297:Male; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D018418:Th2 Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects
D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10