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Interleukin-6 signaling blockade exacerbates acute and late injury from focal intestinal irradiation.

PURPOSE:
To evaluate the acute changes in leukocyte populations after focal irradiation and to assess the role of Interleukin-6 (IL6) in acute and late radiation injury.

METHODS AND MATERIALS:
Mice were surgically implanted with a radiopaque marker on the surface of the small intestine. Mice were then imaged with cone beam computed tomography to locate the marker and irradiated with 18 Gy of 5×5 mm collimated x-rays onto the marked intestine using the Small Animal Radiation Research Platform (SARRP). Intestinal sections and blood were harvested 1, 3.5, 7, 14 days and 2-months post-irradiation (post-IR) for histology and complete blood count, respectively. Immune cell populations were assessed by immunofluorescence in the acute phase. Collagen deposition was assessed 2 months post-IR. IL6-/- intestinal sections were assessed post-IR for morphology, EdU, Ki67, and TUNEL in comparison to IL6+/+ mice. Further, a set of IL6+/+ mice were treated with anti-IL6R to assess the role of IL6 in late intestinal injury.

RESULTS:
Intestinal radiation damage peaked 14 days post-IR and fibrosis had developed by 60 days post-IR. There was a marked infiltration of immune cells into the irradiated intestine with increased neutrophils, macrophages, B-cells, and CD4+ T-cells maintained from 3.5-14 days post-IR. CD8+ T-cells were decreased from days 7-14 post-IR. Systemically, leukocytes were increased in the peripheral blood 14 days post-IR with an anemia being maintained from 14 days-2 months. IL6 was significantly increased in the serum post-IR. IL6-/- mice demonstrated worsened intestinal injury acutely post-IR. Moreover, anti-IL6R treated mice presented with worsened intestinal fibrosis 2 months post-IR.

CONCLUSIONS:
Focal irradiation of the intestine produced a significant increase in immune cells in the irradiated area as well as a systemic inflammation and anemia. Blockade of IL6 signaling was found to exacerbate acute intestinal injury as well as late intestinal injury after focal irradiation.

Bell BI, Koduri S, Salinas CS, Monslow J, Puré E, Ben-Josef E, Koumenis C, Verginadis II.

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