Acute and persisting Th2-like immune response after fractionated colorectal γ-irradiation
Résumé
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. © 2008 The WJG Press. All rights reserved.
Mots clés
chemokine
chemokine receptor CCR4
chemokine receptor CXCR3
cytokine
gamma interferon
gamma interferon inducible protein 10
inducible nitric oxide synthase
interleukin 10
interleukin 1beta
monocyte chemotactic protein 1
STAT3 protein
suppressor of cytokine signaling 3
transcription factor GATA 3
transcription factor T bet
tumor necrosis factor alpha
animal experiment
animal model
animal tissue
article
cell membrane depolarization
cellular immunity
colon mucosa
controlled study
cytokine production
disease course
feedback system
gamma irradiation
histopathology
immunopathogenesis
male
mediator release
nonhuman
protein expression
protein function
radiation dose fractionation
radiation enteropathy
radiation response
rat
rectum
signal transduction
Th1 cell
Th2 cell
Animals
Colon
Dose-Response Relationship
Radiation
Gamma Rays
Immunity
Mucosal
Interleukin-10
Intestinal Mucosa
Male
Models
Animal
Rats
Wistar
Rectum
Signal Transduction
STAT3 Transcription Factor
Suppressor of Cytokine Signaling Proteins
Th1 Cells
Th2 Cells