title: Interleukin 1beta (IL1B) signaling is a critical component of radiation-induced skin fibrosis.
abstract: Interleukin 1 beta (IL1B), a potent pro-inflammatory cytokine, is directly up-regulated by radiation and is known to regulate other inflammation-related molecules, such as the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs). However, the nature of the interaction of IL1B with MMPs and TIMPs in radiation-induced skin fibrosis is unknown. We examined the response of primary dermal keratinocytes, fibroblasts and endothelial cells to single-fraction radiation (10 Gy) and compared the results to a temporal sequence of histology from irradiated C57BL/6 and IL1R1 knockout mice. These studies showed that keratinocytes are the major IL1-producing cells in vitro and that radiation induces an immediate and chronic elevation in the expression of IL1B mRNA in the skin of C57BL/6 mice. This elevation was principally early and was less pronounced in the IL1R1 knockout strain, which also demonstrated reduced late radiation fibrosis. Radiation also increased expression of MMP mRNA in C57BL/6 mice. Finally, exogenous IL1B protein induced robust endogenous IL1B mRNA expression, along with a brisk increase in MMPs and collagen III, but only in the C57BL/6 mice. In conclusion, these data suggest that IL1B plays a critical role in radiation-induced fibrosis and that the increased MMPs fail to block the IL1-related collagen accumulation.
authors.affiliation: Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Ivan
authors.initials: I
authors.lastname: Ding
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Olschowka
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xu
authors.forename: Dongping
authors.initials: D
authors.lastname: Hu
authors.forename: Gary R
authors.initials: GR
authors.lastname: Morrow
authors.forename: Paul
authors.initials: P
authors.lastname: Okunieff
mesh_terms: D000818:Animals; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D005720:Gamma Rays / Q000009:adverse effects; D007375:Interleukin-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011855:Radiodermatitis / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D012867:Skin / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects*
chemical_list: D007375:Interleukin-1