Intestinal Irradiation and Fibrosis in a Th1-Deficient Environment

• Published in: International journal of radiation oncology, biology, physics Vol. 84; no. 1; pp. 266 - 273
• Main Authors: Linard, Christine, Ph.D, Billiard, Fabienne, Ph.D, Benderitter, Marc, Ph.D
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2012; Elsevier
• Subjects: Animals; Biological and medical sciences; Biological effects of radiation; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - radiation effects; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - radiation effects; Cell Differentiation - physiology; Cell Movement - radiation effects; COLLAGEN; Collagen Type III - metabolism; FIBROSIS; Fundamental and applied biological sciences. Psychology; GATA3 Transcription Factor - metabolism; Hematology, Oncology and Palliative Medicine; Ileum - immunology; Ileum - metabolism; Ileum - radiation effects; INTERFERON; Interferon-gamma - metabolism; Interferon-γ; Interleukin-12 - physiology; Interleukin-12 Subunit p35 - metabolism; Interleukin-12 Subunit p40 - metabolism; Interleukin-23 Subunit p19 - metabolism; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - radiation effects; Intestine; INTESTINES; Ionizing radiations; IRRADIATION; Life Sciences; LYMPH NODES; Lymph Nodes - cytology; Mesenteric lymphoid nodes; MESSENGER-RNA; MICE; Mice, Inbred C57BL; MUCOUS MEMBRANES; Radiation; Radiology; RADIOLOGY AND NUCLEAR MEDICINE; RADIOTHERAPY; RNA, Messenger - metabolism; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; STAT4 Transcription Factor - genetics; STAT4 Transcription Factor - metabolism; T-Box Domain Proteins - deficiency; T-Box Domain Proteins - metabolism; Th1 Cells - cytology; Th1 Cells - metabolism; Th1 Cells - radiation effects; Th1 failure; Th2 Cells - cytology; Th2 Cells - metabolism; Th2 Cells - radiation effects; Time Factors; Tissues, organs and organisms biophysics; TOXICITY; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Th1 failure; Interferon-γ; Intestine; Mesenteric lymphoid nodes; Radiation; Toxicity; Th1 lymphocyte; Transcription factor STAT1; Cancerology; Transcription factor STAT4; Radiation effect; Thl failure; Digestive system; Cytokine; Rodentia; Gut; Interleukin 12; Mesentery; Vertebrata; Mammalia; Mouse; Animal; Fibrosis; Irradiation; Radiation injury; Gamma interferon
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2011.11.027

Purpose Changes in the Th1/Th2 immune balance may play a role in increasing the incidence of radiation-induced toxicity. This study evaluates the consequences of Th1 deficiency on intestinal response (fibrosis and T cell trafficking) to abdominal irradiation and examines in mucosa and mesenteric lymph nodes (MLN) the differential involvement of the two Th1 pathways, T-bet/STAT1 and IL-12/STAT4, in controlling this balance in mice. Methods and Materials Using T-bet-deficient mice (T-bet−/− ), we evaluated the mRNA and protein expression of the Th1 pathways (IFN-γ, T-bet/STAT1, and IL-12/STAT4) and the CD4+ and CD8+ populations in ileal mucosa and MLN during the first 3 months after 10 Gy abdominal irradiation. Results The T-bet-deficient mice showed an increased fibrotic response to radiation, characterized by higher TGF-β1, col3a1 expression, and collagen deposition in mucosa compared with wild-type mice. This response was associated with drastically lower expression of IFN-γ, the hallmark Th1 cytokine. Analysis of the Th1 expression pathways, T-bet/STAT1 and IL-12/STAT4, showed their equal involvement in the failure of Th1 polarization. A minimal IFN-γ level depended on the IL-23-p19/STAT4 level. In addition, the radiation-induced deficiency in the priming of Th1 by IFN-γ was related to the defective homing capacity of CD8+ cells in the mucosa. Conclusion Irradiation induces Th2 polarization, and the Th2 immune response may play a role in potentiating irradiation-induced intestinal collagen deposition.