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Cell Signal. 2010 Jul;22(7):1076-87. doi: 10.1016/j.cellsig.2010.02.010. Epub 2010 Mar 3.

Radiation-induced bystander signaling pathways in human fibroblasts: a role for interleukin-33 in the signal transmission.

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  • 1Center for Radiological Research, Department of Radiation Oncology, Columbia University, New York, NY 10032, USA. vni3@columbia.edu

Abstract

The main goal of this study is to elucidate the mechanisms of the signal transmission for radiation-induced bystander response. The NF-kappaB-dependent gene expression of IL8, IL6, PTGS2/COX2, TNF and IL33 in directly irradiated human skin fibroblasts produced the cytokines and prostaglandin E2 (PGE2) with autocrine/paracrine functions, which further activated signaling pathways and induced NF-kappaB-dependent gene expression in bystander cells. As a result, bystander cells also started expression and production of interleukin-8, interleukin-6, COX-2-generated PGE2 and interleukin-33 (IL-33) followed by autocrine/paracrine stimulation of the NF-kappaB and MAPK pathways. A blockage of IL-33 transmitting functions with anti-IL-33 monoclonal antibody added into the culture media decreased NF-kappaB activation in directly irradiated and bystander cells. On the other hand, the IGF-1-Receptor kinase regulated the PI3K-AKT pathway in both directly irradiated and bystander fibroblasts. A pronounced and prolonged increase in AKT activity after irradiation was a characteristic feature of bystander cells. AKT positively regulated IL-33 protein expression levels. Suppression of the IGF-R1-AKT-IL-33 pathway substantially increased radiation-induced or TRAIL-induced apoptosis in fibroblasts. Taken together, our results demonstrated the early activation of NF-kappaB-dependent gene expression first in directly irradiated and then bystander fibroblasts, the further modulation of critical proteins, including IL-33, by AKT in bystander cells and late drastic changes in cell survival and in enhanced sensitivity to TRAIL-induced apoptosis after suppression of the IGF-1R-AKT-IL-33 signaling cascade in both directly irradiated and bystander cells.

(c) 2010 Elsevier Inc. All rights reserved.

PMID:
20206688
[PubMed - indexed for MEDLINE]
PMCID:
PMC2860693
Free PMC Article

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