The role of interleukin-13 in the removal of hyper-radiosensitivity by priming irradiation

Abstract

It has previously been demonstrated that the presence of fetal bovine serum is necessary for TGF-β3 (transforming growth factor beta 3)-dependent elimination of low-dose hyper-radiosensitivity (HRS) in cells by 1 h of low-dose-rate γ-irradiation (0.2–0.3 Gy/h). The purpose of the present study was to identify the serum constituent involved. Two human HRS-positive (T-47D, T98G) cell lines were used. The effects of different pretreatments on HRS were investigated using the colony assay. Total inducible nitric oxide synthase (iNOS) levels were measured using a cell-based ELISA assay. The serum factor was identified as interleukin-13 (IL-13). In order for low dose-rate irradiation to eliminate HRS through the TGF-β3-dependent mechanism, the cells must be exposed to IL-13 first. Inhibiting receptor IL-13Rα2 showed that this receptor is involved in the response. Adding IL-13 to serum-free medium restored the properties of full medium but not when an inhibitor of proprotein convertase activity was added together with IL-13. The presence of IL-13 resulted in upregulation of total iNOS protein levels. Thus, this study indicates that IL-13 interacts with the cells though receptor IL-13Rα2 and induces upregulation of iNOS and activation of one or more furin-like proprotein convertases.

The Role of TGF-β3 in Radiation Response

“…Through a series of studies at our laboratory, LDR priming has been shown to permanently remove HRS from reporter cells in a TGF-β3-dependent mechanism [21,118,[131][132][133][142][143][144]. The change in the amount of active TGF-β3 in LDR primed cells is thought to be small, as the effects resemble closely those produced by treatment with 0.001 ng/mL recombinant TGF-β3, but do not offer protection from radiation doses from 2 to 5 Gy, which is seen after treatment with 0.01 ng/mL TGF-β3.…”

“…In addition to TGF-β3, removal of HRS was found to depend on the action of IL-13 and its receptor IL-13Rα2, inducible nitric oxide synthase (iNOS), and peroxynitrite (ONOO-) [118,143,144]. IL-13 was suggested to be upstream of iNOS, as IL-13Rα2 has been shown to induce iNOS [147,148] and inhibition of IL-13 reduced the amount of total iNOS protein [144]. iNOS produces nitric oxide (NO), which again reacts rapidly with superoxide to produce ONOO-.…”

In vitro stimulatory effect of N‐acetyl tryptophan‐glucopyranoside against gamma radiation induced immunosuppression

“…Radiation is reported to elevate IL‐13 that induced DUOX1 expression; the primary source of sustained ROS production that causes DNA damage . Following low‐dose irradiation, IL‐13 proactivates TGF‐β3 via up‐regulation of iNOS that modulates redox homeostasis of the cells . Therefore, in view of the above cited evidences, immune response modulation/immunosuppression is one of the prime outcomes of irradiation.…”

“…23 Following low-dose irradiation, IL-13 proactivates TGF-b3 via up-regulation of iNOS that modulates redox homeostasis of the cells. 24 Therefore, in view of the above cited evidences, immune response modulation/immunosuppression is one of the prime outcomes of irradiation. Thus, to combat radiation induced immunosuppression, a radioprotective agent that modulates the immune response in irradiated cells is an unavoidable requirement particularly for the cancer patients undergoing radiotherapy regime.…”