The long-term tissue response following ionizing irradiation (IR) involves molecular events in different cell types that regulate tissue homeostasis that has implications for inflammation, tissue damage and cancer. We have previously shown that loss of DR5/Killer/MK, the receptor to the cytokine Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL) in mice confers resistance to acute cell death inflicted by IR in several lymphoid and also to some extent in non-lymphoid organs (Finnberg N et al. Mol. Cell. Biol. 25:2000-2013, 2005). In the present study we explored the long-term effects (17 months) of IR in mice treated with a single sub-lethal dose of whole-body irradiation (4 Gy) at the age of 4-5 weeks. Wild-type (wt, N = 11) mice, mice heterozygous for the DR5 receptor (DR5, N = 10) and mice completely lacking the DR5-receptor (DR5-/-, N = 21) were subjected to irradiation. Increased lethality was observed in the DR5-/- group at 8 months following IR. Necropsy showed “tissue damage” (i.e., infiltrating lymphocytes, fibrosis and distorted tissue architecture) in the lungs (consistent with bronchopneumonia), small intestine and the colon of moribund DR5-/- mice. Immunohistochemistry identified infiltrating lymphocytes as CD3-positive, deposition of fibronectin and increased numbers of TUNEL-positive epithelial cells in damaged tissue. A limited number of tumors were detected in the lungs and the lymphoid tissues of DR5-/- mice and DR5 mice (but not wt mice) that survived 17 months. We propose a model wherein DR5 functions as a negative regulator of late tissue-damage involving inflammation and fibrosis following IR primarily in the lungs. In addition, TRAIL might be useful in modulating the tissue toxicity following anti-cancer therapy. Thus DR5 appears to suppress chronic inflammation and cancer following exposure to IR.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]