A1906 Effect of Asbestos on Transcription Factor Foxo1

Monday, March 19, 2012
Ground Floor (Cancun Center)
Hidenori Matsuzaki, Department of Hygiene, Kawasaki Medical Scool, Kurashiki, Japan
Megumi Maeda, Division of Bioscience, Department of Biofunctional Chemistry, Okayama University, Graduate School of Natural Science and Technology, Okayama, Japan
Sehoon Lee, Department of Hygiene, Kawasaki Medical Scool, Kurashiki, Japan
Naoko Kumagai, Department of Hygiene, Kawasaki Medical School, Kurashiki, Japan
Yasumitsu Nishimura, Department of Hygiene, Kawasaki Medical School, Kurashiki, Japan
Takemi Otsuki, Department of Hygiene, Kawasaki Medical School, Kurashiki, Japan
Introduction
Asbestos is known to cause mesothelioma and lung cancer. We previously reported that asbestos affects not only mesothelial and lung epitheial cells, but also anti-tumor immune system. Regulatory T cell, Treg, produces inhibitory cytokines to suppress anti-tumor immune system. We found that asbestos enhanced Treg function by using MT-2 cell line, which is an HTLV-transformed human FoxP3 positive Treg model cell line. In this study, effect of asbestos on gene expression pattern in MT-2 cells was analyzed by micro array analysis.

Methods
MT-2 cells were cultured with asbestos for 8 months to establish in vitro Treg model of long term exposure to asbestos. Resulting sub-lines show resistance to asbestos and produces inhibitory cytokines, IL-10 and TGFβ, at a high level and were designated as MT-2 Resistant (MT-2Rst). Total RNA were prepared from MT-2Rst and control MT-2 cells, respectively, and mRNA expressed in these cells were analyzed by using a micro array containing 41,000 human genes.

Results
Micro array analysis revealed that total 139 genes were significantly altered in MT-2Rst cells (greater than 2 fold changes). Namely, 84 genes were up-regulated and 55 genes were down-regulated, and most of them were categorized as cellular component, biological process and molecular function group by Gene Ontology analysis. Forkhead transcription factor FoxO1 was found as down-regulated gene. Reduction of FoxO1 mRNA was confirmed by RT-PCR. Furthermore, immunoblot analysis showed FoxO1 protein decreased in MT-2Rst.

Discussion
FoxO1 is concidered to be activated by oxidative stress to regulate apoptosis. Recently, it was reported that FoxO1 controls development of Treg through the expression of FoxP3 in mouse. In this study, we found that FoxO1 is down-regulated after long term exposure to asbestos in MT-2 cells. These findings suggest that FoxO1 regulates asbestos-induced apoptosis and/or producing inhibitory cytokines to regulate anti-tumor immune system.

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