Effect of IL-15 addition on asbestos-induced suppression of human cytotoxic T lymphocyte induction

BACKGROUND@#Asbestos fibers possess tumorigenicity and are thought to cause mesothelioma. We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. Asbestos exposure in the mixed lymphocyte reaction (MLR) showed suppressed induction of cytotoxic T lymphocytes (CTLs), accompanied by a decrease in proliferation of CD8@*METHODS@#For MLR, human peripheral blood mononuclear cells (PBMCs) were cultured with irradiated allogenic PBMCs upon exposure to chrysotile B asbestos at 5 μg/ml for 7 days. After 2 days of culture, IL-15 was added at 1 ng/ml. After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8@*RESULTS@#IL-15 addition partially reversed the decrease in CD3@*CONCLUSION@#These findings indicate that CTLs induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation, and that IL-15 is more effective in the recovery of proliferation and granzyme B levels from asbestos-induced suppression of CTL induction compared with IL-2.

Effect of asbestos exposure on differentiation and function of cytotoxic T lymphocytes

Asbestos exposure is known to cause malignant mesothelioma, which is associated with poor prognosis. We focused on and examined the effect of asbestos exposure on the differentiation and function of cytotoxic T lymphocytes (CTLs). CTLs have the ability to specifically attack tumor cells after being differentiated from naïve CD8 T cells following antigen stimulation. Exposure to chrysotile B asbestos suppressed the differentiation of CTLs during the mixed lymphocyte reaction (MLR) and was associated with a decrease in proliferation of CD8 T cells. Additionally, in an effort to investigate the mechanism associated with suppressed CTL differentiation upon exposure to asbestos, we focused on IL-2, a cytokine involved in T cell proliferation. Our findings indicated that insufficient levels of IL-2 are not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest potential improvement in the suppressed CTL function. Furthermore, the functional properties of peripheral blood CD8 lymphocytes from asbestos-exposed individuals with pleural plaque (PP) and patients with malignant mesothelioma (MM) were examined. MM patients showed lower perforin levels in CD8 lymphocytes following stimulation compared with PP-positive individuals. The production capacity of IFN-γ in the MM group tended to be lower compared with healthy volunteers or PP-positive individuals. In an effort to determine whether chronic and direct asbestos exposure affected the function of CD8 T cells, cultured human CD8 T cells were employed as an in vitro model and subjected to long-term exposure to chrysotile (CH) asbestos. This resulted in decreased levels of intracellular perforin and secreted IFN-γ. Those findings underlie the possibility that impaired CD8 lymphocyte function is caused by asbestos exposure, which fail to suppress the development of MM. Our studies therefore reveal novel effects of asbestos exposure on CTLs, which might contribute towards the development and implementation of an effective strategy for the prevention and cure of malignant mesothelioma.

For making a declaration of countermeasures against the falling birth rate from the Japanese Society for Hygiene: summary of discussion in the working group on academic research strategy against an aging society with low birth rate

In 1952, the Japanese Society for Hygiene had once passed a resolution at its 22nd symposium on population control, recommending the suppression of population growth based on the idea of cultivating a healthier population in the area of eugenics. Over half a century has now passed since this recommendation; Japan is witnessing an aging of the population (it is estimated that over 65-year-olds made up 27.7% of the population in 2017) and a decline in the birth rate (total fertility rate 1.43 births per woman in 2017) at a rate that is unparalleled in the world; Japan is faced with a "super-aging" society with low birth rate. In 2017, the Society passed a resolution to encourage all scientists to engage in academic researches to address the issue of the declining birth rate that Japan is currently facing. In this commentary, the Society hereby declares that the entire text of the 1952 proposal is revoked and the ideas relating to eugenics is rejected. Since the Society has set up a working group on the issue in 2016, there have been three symposiums, and working group committee members began publishing a series of articles in the Society's Japanese language journal. This commentary primarily provides an overview of the findings from the published articles, which will form the scientific basis for the Society's declaration. The areas we covered here included the following: (1) improving the social and work environment to balance between the personal and professional life; (2) proactive education on reproductive health; (3) children's health begins with nutritional management in women of reproductive age; (4) workplace environment and occupational health; (5) workplace measures to counter the declining birth rate; (6) research into the effect of environmental chemicals on sexual maturity, reproductive function, and the children of next generation; and (7) comprehensive research into the relationship among contemporary society, parental stress, and healthy child-rearing. Based on the seven topics, we will set out a declaration to address Japan's aging society with low birth rate.

Decrease in Serum Amyloid a Protein Levels Following Three-month Stays in Negatively Charged Particle-dominant Indoor Air Conditions / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>The changes in serum adipokines and cytokines related to oxidative stress were examined during 3 months 'Off to On' and 'On to Off' periods using negatively charged particle-dominant indoor air conditions (NCPDIAC).</p><p><b>METHODS</b>Seven volunteers participated in the study, which included 'OFF to 3 months ON' periods (ON trials) for a total of 16 times, and 'ON to 3 months OFF' (OFF trials) periods for a total of 13 times.</p><p><b>RESULTS</b>With the exception of one case, serum amyloid A (SAA) levels decreased significantly during the ON trials.</p><p><b>CONCLUSION</b>Considering that SAA is an acute phase reactive protein such as C reactive protein (CRP), this observed decrease might indicate the prevention of cardiovascular and atherosclerotic changes, since an increase in high-sensitive CRP is associated with the subsequent detection of these events.</p>

Biological Effects of Cloth Containing Specific Ore Powder in Patients with Pollen Allergy / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>The custom-homebuilding company, Cosmic Garden Co. Ltd., located in Okayama City, Japan was established in 1997 and uses specific natural ore powder (SNOP) in wall materials and surveys customers in order to improve allergic symptoms.</p><p><b>METHODS</b>To investigate the biological effects of SNOP, patients with a pollen allergy were recruited to stay in a room surrounded by cloth containing SNOP (CCSNOP), and their symptoms and various biological parameters were compared with those of individuals staying in a room surrounded by control non-woven cloth (NWC). Each stay lasted 60 min. Before and immediately after the stay, a questionnaire regarding allergic symptoms, as well as POMS (Profile of Mood Status) and blood sampling, was performed. Post-stay minus pre-stay values were calculated and compared between CCSNOP and NWC groups.</p><p><b>RESULTS</b>Results indicated that some symptoms, such as nasal obstruction and lacrimation, improved, and POMS evaluation showed that patients were calmer following a stay in CCSNOP. Relative eosinophils, non-specific Ig E, epidermal growth factor, monocyte chemotactic protein-1, and tumor necrosis factor-α increased following a stay in CCSNOP.</p><p><b>CONCLUSION</b>This ore powder improved allergic symptoms, and long-term monitoring involving 1 to 2 months may be necessary to fully explore the biological and physical effects of SNOP on allergic patients.</p>

Cytokine alteration and speculated immunological pathophysiology in silicosis and asbestos-related diseases

This review is partly composed of the presentation "Cytokine alteration and speculated immunological pathophysiology in silicosis and asbestos-related diseases" delivered during the symposium "Biological effects of fibrous and particulate substances and related areas" organized by the Study Group of Fibrous and Particulate Studies of the Japanese Society of Hygiene and held at the 78th Annual Meeting in Kumamoto, Japan. In this review, we briefly introduce the results of recent immunological analysis using the plasma of silica and asbestos-exposed patients diagnosed with silicosis, pleural plaque, or malignant mesothelioma. Thereafter, experimental background and speculation concerning the immunological pathophysiology of silica and asbestos-exposed patients are discussed.

Immunological alterations found in mesothelioma patients and supporting experimental evidence

It is common knowledge that exposure to asbestos causes asbestos-related diseases, such as asbestosis, lung cancer and malignant mesothelioma, not only in people who have had long-term contact with asbestos in their work environment but also in residents living near factories that handle asbestos. Since the summer of 2005, these revelations turned into a large medical problem and caused and social unrest. We have focused on the immunological effects of both asbestos and silica on the human immune system. In this brief review, we introduce immunological alterations found in patients with malignant mesothelioma and describe the experimental background in which these were found. Analyzing the immunological effects of asbestos may improve our understanding of the biological effects of asbestos.

Keynote lecture in the 13th Japanese Society of Immunotoxicology (JSIT 2006) : -Pathophysiological Development and Immunotoxicology: what we have found from research related to silica and silicate such as asbestos-

Silica and silicates may disturb immune functions such as autoimmunity and tumor immunity, because people who are exposed to the materials sometimes develop autoimmune and malignant diseases, respectively. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer in 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate the nation wide anxiety about these malignancies.

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

Silica and silicates may disturb immune functions such as autoimmunity and tumor immunity, because people who are exposed to the materials sometimes develop autoimmune and malignant diseases, respectively. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer in 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate the nation wide anxiety about these malignancies.

The inhibitory effect of dibutyryl cyclic AMP on docosahexaenoic acid-induced apoptosis in HL-60 cells through activation of the phosphatidylinositol-3 kinase pathway

<p><b>OBJECTIVE</b>Docosahexaenoic acid (DHA) is known as a chemopreventive substance for cancers. Previously we reported that DHA induces apoptosis in HL-60 cells. The aim of this study was to clarify the role of phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling during DHA-induced apoptosis in HL-60 cells.</p><p><b>METHODS</b>The inhibitory effects of dibutyryl cAMP (db-cAMP) or LY294002 (a specific inhibitor of the PI3-kinase/Akt pathway) on DHA-induced apoptosis in HL-60 cells were evaluated by the appearance of apoptosis, and from the activities of caspases (3 and 8), the phospholylation of Akt, and cleavage of Bid using DNA indexes, emzymatic measurement of fragmented substrates, and Western blotting, respectively.</p><p><b>RESULTS</b>The pre-incubation of db-cAMP reduced the activation of caspasses (3 and 8) during the occurrence of DHA-induced apoptosis in HL-60. However, the inhibition of PI3-kinase/Akt signaling by LY294002 resulted in recovery of the caspases' activities, appearance of apoptotic cells, and cleavage of the Bid molecule when LY294002 was co-treated with db-cAMP before the occurrence of DHA-induced apoptosis in HL-60. It was also confirmed that LY294002 strongly inhibited phospholylation of Akt during db-cAMP induced-reduction of DHA-induced apoptosis in HL-60.</p><p><b>CONCLUSION</b>We demonstrated that DHA-induced apoptosis was sensitive to the modulation of PI3-kinase activity by treatment with db-cAMP or LY294002. These results may provide new insights into the mechanisms of the anti-cancer activity of DHA.</p>

The Inhibitory Effect of Dibutyryl Cyclic AMP on Docosahexaenoic Acid-Induced Apoptosis in HL-60 Cells through Activation of the Phosphatidylinositol-3 Kinase Pathway

Objective: Docosahexaenoic acid (DHA) is known as a chemopreventive substance for cancers. Previously we reported that DHA induces apoptosis in HL-60 cells. The aim of this study was to clarify the role of phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling during DHA-induced apoptosis in HL-60 cells. Methods: The inhibitory effects of dibutyryl cAMP (db-cAMP) or LY294002 (a specific inhibitor of the PI3-kinase/Akt pathway) on DHA-induced apoptosis in HL-60 cells were evaluated by the appearance of apoptosis, and from the activities of caspases (3 and 8), the phospholylation of Akt, and cleavage of Bid using DNA indexes, emzymatic measurement of fragmented substrates, and Western blotting, respectively. Results: The pre-incubation of db-cAMP reduced the activation of caspasses (3 and 8) during the occurrence of DHA-induced apoptosis in HL-60. However, the inhibition of PI3-kinase/Akt signaling by LY294002 resulted in recovery of the caspases’ activities, appearance of apoptotic cells, and cleavage of the Bid molecule when LY294002 was co-treated with db-cAMP before the occurrence of DHA-induced apoptosis in HL-60. It was also confirmed that LY294002 strongly inhibited phospholylation of Akt during db-cAMP induced-reduction of DHA-induced apoptosis in HL-60. Conclusion: We demonstrated that DHA-induced apoptosis was sensitive to the modulation of PI3-kinase activity by treatment with db-cAMP or LY294002. These results may provide new insights into the mechanisms of the anti-cancer activity of DHA.

Perturbation of secretory Ig A in saliva and its daily variation by academic stress

<p><b>OBJECTIVES</b>Several studies have reported that the secretory immunoglobulin A (S-IgA) concentration in saliva is an indicator of psychological stress. The aim of this study was to clarify the relationship between S-IgA and the stress from academic examinations.</p><p><b>METHODS</b>S-IgA levels in 10 medical student volunteers from the second year course between May 4 and July 13, 2000 were examined using the ELISA method.</p><p><b>RESULTS</b>There was a tendency for S-IgA in saliva to be higher on the day before academic examinations and during them, and lower on the days between these examinations.</p><p><b>CONCLUSIONS</b>It may be possible to use this measurement to monitor psychological stress in students and workers.</p>

Detection of anti-topoisomerase I autoantibody in patients with silicosis

<p><b>OBJECTIVES</b>The aim of this study was to detect anti-topoisomerase I (anti-topo I) autoantibodies, which are known to be limited in systemic sclerosis patients, in silicosis patients with no clinical symptoms of autoimmune disease.</p><p><b>METHODS</b>Serum anti-topo I autoantibodies were detected using ELISA. Differences in clinical parameters between patients with and without anti-topo I autoantibodies were analyzed.</p><p><b>RESULTS</b>Seven of 69 patients had anti-topo I autoantibodies. These 7 patients showed elevated PaCO(2) values (P=0.0212), and inverse correlations between serum soluble Fas levels and PaCO(2) values were found.</p><p><b>CONCLUSION</b>Anti-topo I autoantibodies were detected in 10.1% of silicosis patients without any clinical symptoms of autoimmune disease. The findings here suggest that the genesis of anti-topo I autoantibodies might be related to pulmonary involvement or lung fibrosis associated with progression of silicosis.</p>

Detection of Anti-Topoisomerase I Autoantibody in Patients with Silicosis

Objectives: The aim of this study was to detect anti-topoisomerase l (anti-topo I) autoantibodies, which are known to be limited in systemic sclerosis patients, in silicosis patients with no clinical symptoms of autoimmune disease. Methods: Serum anti-topo I autoantibodies were detected using ELISA. Differences in clinical parameters between patients with and without anti-topo I autoantibodies were analyzed. Results: Seven of 69 patients had anti-topo I autoantibodies. These 7 patients showed elevated PaCO2 values (P=0.0212), and inverse correlations between serum soluble Fas levels and PaCO2 values were found. Conclusion: Anti-topo I autoantibodies were detected in 10.1% of silicosis patients without any clinical symptoms of autoimmune disease. The findings here suggest that the genesis of anti-topo l autoantibodies might be related to pulmonary involvement or lung fibrosis associated with progression of silicosis.

Perturbation of Secretory Ig A in Saliva and Its Daily Variation by Academic Stress

Objectives: Several studies have reported that the secretory immunoglobulin A (S-IgA) concentration in saliva is an indicator of psychological stress. The aim of this study was to clarify the relationship between S-IgA and the stress from academic examinations. Methods: S-IgA levels in 10 medical student volunteers from the second year course between May 4 and July 13, 2000 were examined using the ELISA method. Results: There was a tendency for S-IgA in saliva to be higher on the day before academic examinations and during them, and lower on the days between these examinations. Conclusions: It may be possible to use this measurement to monitor psychological stress in students and workers.