title: Radiation-induced bystander signaling pathways in human fibroblasts: a role for interleukin-33 in the signal transmission.
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.
authors.affiliation: Center for Radiological Research, Department of Radiation Oncology, Columbia University, New York, NY 10032, USA. vni3@columbia.edu
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Ivanov
authors.forename: Hongning
authors.initials: H
authors.lastname: Zhou
authors.forename: Shanaz A
authors.initials: SA
authors.lastname: Ghandhi
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Karasic
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yaghoubian
authors.forename: Sally A
authors.initials: SA
authors.lastname: Amundson
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D024201:Bystander Effect; D018797:Cell Cycle Proteins / Q000502:physiology; D002470:Cell Survival; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects*; D015870:Gene Expression; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C506536:IL33 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D036341:Intercellular Signaling Peptides and Proteins; D000067596:Interleukin-33; D007378:Interleukins; D047908:Intracellular Signaling Peptides and Proteins; D017978:Receptors, Growth Factor; D017451:Receptors, Somatomedin; D053221:TNF-Related Apoptosis-Inducing Ligand; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C546842:MTOR protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases