Involvement of IL-10 and Bcl-2 in resistance against an asbestos-induced apoptosis of T cells

Abstract

To analyze the possibility that immunological alteration in asbestos-related diseases (ARDs) such as asbestosis (ASB) and malignant mesothelioma (MM) may affect the progression of cancers, a human adult T cell leukemia virus-immortalized T cell line (MT-2Org) was continuously exposed to 10 µg/ml of chrysotile-B (CB), an asbestos. After at least 8 months of exposure, the rate of apoptosis in the cells became very low and the resultant subline was designated MT-2Rst. The MT-2Rst cells were characterized by (i) enhanced expression of bcl-2, with regain of apoptosis-sensitivity by reduction of bcl-2 by siRNA, (ii) excess IL-10 secretion and expression, and (iii) activation of STAT3 that was inhibited by PP2, a specific inhibitor of Src family kinases. These results suggested that the contact

Keynote lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006)

“…These findings suggest that contact between cells and asbestos may affect the human immune system and trigger a cascade of biological events, such as the activation of Src family kinases, enhancement of IL-10 expression, STAT3 activation, and Bcl-2 overexpression, as shown on the right side of Fig. 2 and as previously reported (70). This speculation was partially confirmed by the detection of higher bcl-2 expression levels in CD4+ peripheral blood T cells from patients with malignant mesothelioma than in those from patients with asbestosis or from HDs (70).…”

“…2 and as previously reported (70). This speculation was partially confirmed by the detection of higher bcl-2 expression levels in CD4+ peripheral blood T cells from patients with malignant mesothelioma than in those from patients with asbestosis or from HDs (70).…”

“…The MT-2Rst cells were characterized by (i) an enhanced expression of bcl-2, restoring apoptosis sensitivity with the decrease in bcl-2 expression level by siRNA (70), (ii) an excessive IL-10 secretion and expression (70), and (iii) the activation of STAT3 inhibited by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolol [3,4-d] pyrimidine (PP2), a specific inhibitor of Src family kinases (70). These findings suggest that contact between cells and asbestos may affect the human immune system and trigger a cascade of biological events, such as the activation of Src family kinases, enhancement of IL-10 expression, STAT3 activation, and Bcl-2 overexpression, as shown on the right side of Fig.…”

Role of Inflammation and Angiogenic Growth Factors in Malignant Mesothelioma

“…This apparent paradox is reconciled by the current hypothesis that the chronic inflammation induced by asbestos leads to the persistent activation of the nuclear factor kappa B (NF-κB) transcription factor, which in turn mediates the activation of prosurvival genes and prevents apoptosis of the damaged mesothelial cells (Mantovani et al, 2008;Micheau & Tschopp, 2003;Philip et al, 2004). This allows mesothelial cells with asbestos-induced DNA damage to survive and divide rather than die and, if sufficient genetic damage accumulates, to eventually develop into a MM (Miura et al, 2006;Nymark, 2007). In fact, apoptosis is an important mechanism by which cells with DNA damage are eliminated without eliciting an inflammatory response (Ullrich et al, 2008;Yoshida et al, 2010).…”

FoxO1 regulates apoptosis induced by asbestos in the MT-2 human T-cell line

“…In our earlier studies, MT-2 -a polyclonal T-cell line immortalized with human adult leukemia virus-1 -was cultured with a low concentration of chrysotile A, chrysotile B or crocidolite for 48 months (Miura et al 2006;Maeda et al 2011Maeda et al , 2012. The resultant seven independent sub-lines were designated CA (chrysotile A) 1-3, CB (chrysotile B) 1-3 and CR (crocidolite).…”