Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33 secreted from impaired vessels in the skin compared to fractionated irradiation.

Abstract

We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm(2) fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C-C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA-sequencing using 30 Gy-irradiated mouse skin and functional assays in a co-culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-β, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil-mediated fibrosis in high-dose-per fraction irradiated skin.

• Authors: Eun-Jung Lee, Jun Won Kim, Hyun Yoo, Woori Kwak, Won Hoon Choi, Seoae Cho, Yu Jeong Choi, Yoon-Jin Lee, Jaeho Cho
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 464 Issue 1 Pg. 20-6 (Aug 14 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26047701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies
• Chemokine CCL11
• Il33 protein, mouse
• Interleukin-33
• Interleukin-5
• Interleukins
• Transforming Growth Factor beta
• Interleukin-4

Topics

• Animals
• Antibodies (pharmacology)
• Cell Movement (drug effects, radiation effects)
• Chemokine CCL11 (genetics, metabolism)
• Coculture Techniques
• Dose-Response Relationship, Radiation
• Eosinophils (drug effects, metabolism, pathology, radiation effects)
• Female
• Fibrosis
• Gene Expression
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism, pathology, radiation effects)
• Humans
• Interleukin-33
• Interleukin-4 (genetics, metabolism)
• Interleukin-5 (genetics, metabolism)
• Interleukins (antagonists & inhibitors, genetics, metabolism)
• Macrophages (drug effects, metabolism, pathology, radiation effects)
• Mice
• Radiation Dosage
• Skin (blood supply, drug effects, pathology, radiation effects)
• Swine
• Transforming Growth Factor beta (genetics, metabolism)
• X-Rays