**6. Conclusion**

suspected, Bcl-2 silenced cells exhibited much higher apoptosis and growth inhibition. Thus, the Src ➔ IL-10 ➔ STAT3 ➔ Bcl-2 axis was considered important for the acquisition of resistance to asbestos-induced apoptosis in MT-2 CE [31, 34]. Additionally, CD4-positive peripheral blood cells from asbestos-exposed patients exhibiting pleural plaque (PP) or malignant mesothelioma (MM) showed enhanced expression of Bcl-2 compared with that of healthy volunteers (HV). Thus, the MT-2 CE model may express events occurring within T cells of

Sublines continuously exposed to asbestos were established independently and comprised six sublines exposed to CH and three sublines exposed to CR. The profiles of cytokine production in these MT-2 CEs (exposed to CH or CR) were similar [31, 33, 35]. Continuous exposure caused excess production of IL-10 (as mentioned earlier) and transforming growth factor (TGF)-β, whereas interferon (IFN)-γ production was reduced in MT-2 CEs compared to that in MT-2Org. In addition, Bcl-2 upregulation was found in all MT-2 CEs and there were no differences between exposure to CH and CR [31, 33, 35]. In fact, a cDNA microarray assay using MT-2 CEs and MT-2org indicated that most of the upregulated and downregulated genes were similar in MT-2 CEs. Therefore, these MT-2 CEs could be used as a continuously

The cDNA microarray assay revealed that the transcription factor forkhead box O1 (FoxO1) was expressed to a lesser degree in MT-2 CE compared to MT-2Org [36]. FoxO1 is known to regulate various genes in apoptosis, metabolism, cell growth and differentiation, and so on. In particular, FoxO1 controls various proapoptotic genes such as the p53 upregulated modulator of apoptosis (Puma), bcl-2 interacting mediator of cell death (Bim), and the Fas ligand (FasL) [36, 37]. The message expression of these proapoptotic molecules was reduced in MT-2 CE compared with that in MT-2Org (shown on the right side of **Figure 1**). In addition, following knockdown of the FoxO1 gene in MT-2Org, the level of apoptotic cells caused by transient and high-dose exposure to asbestos was reduced. Furthermore, when the expression of FoxO1 was forced in MT-2 CE, the ratio of apoptosis increased following transient and

These results indicated that acquisition of resistance to asbestos-induced apoptosis by continuous and low-dose exposure to asbestos was regulated by the FoxO1 transcription factor

The purpose of establishing a cell line model involving continuous and relatively low-dose exposure of human T cells to asbestos fibers was to investigate cellular and molecular alterations that may reflect the immune function in human populations exposed to asbestos as well

A consideration of the development of cancer in asbestos-exposed patients suggested that

high-dose exposure to asbestos and the expression of Puma was recovered [36].

in addition to the Src ➔ IL-10 ➔ STAT3 ➔ Bcl-2 axis [31–36].

**5. Findings in MT-2CEs regarding antitumor immunity**

focus within investigations should be placed on antitumor immunity.

asbestos-exposed patients [31, 34].

14 Cytotoxicity

asbestos-exposed immune T cell model.

as patients exhibiting PP or MM.

Investigation of cytotoxicity in human T cells caused by asbestos exposure indicated that the production of ROS and activation of the mitochondrial apoptotic pathway were the main causes for apoptosis of T cells following a transient and relatively high-dose exposure [32], similar to known mechanisms investigated previously using alveolar epithelial and pleural mesothelial cells [5–9, 44–46]. However, the continuous and relatively low-dose exposure of T cells to asbestos altered cellular and molecular events that caused acquisition of resistance against asbestosinduced cytotoxicity. Investigations revealed the importance of the Src ➔ IL-10 ➔ STAT3 ➔ Bcl-2 axis as well as the reduced expression of FoxO1 [31, 33–35]. These changes induce the reduction of antitumor immunity in an asbestos-exposed population and create an increased risk of carcinogenicity due to the transforming activity associated with asbestos fibers [44–46].

Considering the most important issue in asbestos-exposed population, the occurrence of malignancies such as mesothelioma and lung cancer after long-term latent period should be explored the mechanisms as well as be prevented [1–4]. Thus, regarding the cytotoxic effects of asbestos fibers onto human T cell, the acquisition of reduced antitumor immunity caused by continuous exposure to fibers should be focused, since it may be possible to dissolve or recover this situation. As a result, some preventive ways for asbestos-induced cancers in exposed population will be identified.

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Recovery of cellular and molecular changes in asbestos-exposed T cells using certain food constituents or physiologically active substances, including plants or other materials, may support the maintenance of antitumor activity in an asbestos-exposed population and might help to reduce the chances of carcinogenesis caused by asbestos fibers.
