Interleukin 1beta (IL1B) signaling is a critical component of radiation-induced skin fibrosis.
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.
Liu
Weimin
W
Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
Ding
Ivan
I
Chen
Keqiang
K
Olschowka
John
J
Xu
Jianhua
J
Hu
Dongping
D
Morrow
Gary R
GR
Okunieff
Paul
P
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*
D007375:Interleukin-1