Sep 24, 2012

Yi Shang (National Institute of Radiological Sciences)

Interleukin-9 (IL-9) is a multifunctional cytokine that not only has roles in immune and inflammatory responses but also is involved in growth-promoting and anti-apoptotic activities in multiple transformed cell lines, which suggests a potential role in tumorigenesis. Over-expression of the receptor of IL-9 (IL-9R) occurs in several types of human leukemias and in radiation-induced mouse T-cell lymphoma (TL). The molecular mechanism that regulates transcription of the IL-9R gene (Il9r) during leukemogenesis is, however, not well understood. Using a mouse TL cell line that has high expression of Il9r, we sought to dissect its promoter structure. Here we show that the active promoter for Il9r is located in the 5¢-flanking AT-rich region. Chromatin immunoprecipitation showed the opening of chromatin structure of the promoter region coupled with nucleolin binding in vivo. Immunohistochemical analysis confirmed the increased localization of nucleolin in the nuclei of TL cells. These data indicate that increased expression of Il9r is associated with an increased binding of nucleolin, coupled with chromatin opening, to an AT-rich region in the 5'-flanking region of Il9r in TL cells. 

References:
Yi Shang, Shizuko Kakinuma, Mayumi Nishimura, Yoshiro Kobayashi, Kisaburo Nagata and Yoshiya Shimada. Interleukin-9 Receptor Gene is Transcriptionally Regulated by Nucleolin in T-Cell Lymphoma Cells. 
Mol Carcinog 51:619–627 (2012)

Aug 22, 2012

Hironori YOSHINO (Hirosaki University Graduate School of Health Sciences)

Dendritic cells (DCs) are a type of antigen-presenting cell which play an essential role in the immune system. Recent immunotherapeutic research has been focused on the use of DCs as potential cellular vaccines against malignant tumors. However, little is known whether the DCs generation is affected after chemotherapy and radiotherapy. In particular, the influence of ionizing radiation remains to be elucidated. We have recently reported that X-irradiated monocytes, which are precursors of DCs, can differentiate into immature DCs (iDCs) and then mature after TNF-α stimulation in terms of surface antigens expression, while their functions such as the ability to stimulate allogeneic T cells are attenuated. (J. Radiat. Res., 49, 2008). Recent reports propose various types of maturation stimuli, including proinflammatory cytokines and pathogen-derived components on processing DCs for immunotherapies. Therefore, the present study investigated whether X-irradiation of monocytes influenced the maturation of DCs in response to specific maturation stimuli. Human monocytes separated from buffy coats were exposed to X-rays and were then differentiated into iDCs. iDCs were stimulated by lipopolysaccharide (LPS) or proinflammatory cytokine mixture (MIX). The DCs from nonirradiated and X-irradiated monocytes showed maturation after LPS and MIX stimulation as confirmed by findings of surface antigen expression. Upon LPS stimulation, however, the expression levels of CD80 and CD83 on the DCs from the X-irradiated monocytes were lower than those of the DCs from the nonirradiated monocytes. Such reductions were not observed upon MIX stimulation. Similarly, an impairment of matrix metalloproteinase-9 and cytokine production was observed in the LPS-stimulated DCs from the X-irradiated monocytes, whereas these impairments were not observed upon MIX stimulation. The ability of DCs to stimulate T cells was lower in the irradiated group compared with the nonirradiated group despite the type of maturation stimulus. Thus, the present results suggest that the influence of X-irradiation on the maturation of DCs depends on the type of maturation stimulus used and that X-irradiation especially impairs the response of DCs to LPS.

References:
Yoshino H and Kashiwakura I. Impairment of mature dendritic cells derived from X-irradiated human monocytes depends on the type of maturation stimulus used. 
Radiat Res. 2012 Aug 10. [Epub ahead of print] 

Aug 22, 2012

Shinobu Hirano (National Institute of Radiological Sciences, Juntendo University)

Cancer risk from radiation in humans is considered to result from simultaneous exposure to natural and manmade carcinogens. Available data are insufficient on the molecular characteristics of cancer after simultaneous exposure to radiation and chemicals. In this study, we used a mouse thymic lymphoma (TL) model that was synergistically induced by simultaneous exposure to X-rays and N-ethyl-N-nitrosourea (ENU) at sub-carcinogenic doses and analyzed the mutation frequency and spectrum of the TL-associated genes Ikaros, Notch1, p53, and Kras. We found that the point mutation frequency in Ikaros was significantly increased to 47% for simultaneous exposure, as compared with 13% and 0% for X-ray and ENU exposure alone, respectively. These mutations were mostly G:C > A:T at non-CpG sites and T:A > C:G, both of which are characteristic of ENU mutagenesis. About half of the point mutations were accompanied by loss of heterozygosity (LOH), typical of X-irradiation. The remaining half did not include LOH, which suggests they were dominant-negative mutations. In Notch1, the abnormality frequency was high (>58%) regardless of the treatment, suggesting that Notch1 aberration may be important for T-cell lymphomagenesis. The p53 and Kras mutation frequencies were low for all treatments (<23%). Importantly, the frequency of TLs containing mutations in multiple genes, especially both Ikaros and Notch1, increased after simultaneous exposure. Thus, after simultaneous exposure, Ikaros is a critical target and is inactivated by ENU–induced point mutations and/or X-ray–induced LOH in T-cell lymphomagenesis. Furthermore, concomitant alterations of multiple tumor-associated genes may contribute to enhanced lymphomagenesis after simultaneous exposure.

References:
Hirano S, Kakinuma S, Amasaki Y, Nishimura M, Imaoka T, Fujimoto S, Hino O, Shimada Y. Ikaros is a critical target during simultaneous exposure to X-rays and N-ethyl-N-nitrosourea in mouse T-cell lymphomagenesis. 
Int J Cancer. 2012 Jun 9. doi: 10.1002/ijc.27668. [Epub ahead of print]

Apr 01, 2012

Takahiro KATAOKA (Graduate School of Health Sciences, Okayama University)

There have been no reports on anti-inflammatory effects of radon inhalation. The purpose of this study was to determine whether radon inhalation has anti-inflammatory effects in mice. Carrageenan (1% v/v) was injected subcutaneously into paws of mice that had or had not inhaled approximately 2,000 Bq/m3 of radon for 24 hours. Radon inhalation significantly increased superoxide dismutase (SOD) and catalase activities and significantly decreased lipid peroxide levels in mouse paws, indicating that radon inhalation activates antioxidative functions. Carrageenan administration induced paw edema and significantly increased tumor necrosis factor-alpha (TNF-α) and nitric oxide in serum. However, radon inhalation significantly reduced carrageenan-induced paw edema. Serum TNF-α levels were lower in the radon-treated mice than in sham-treated mice. These findings indicated that radon inhalation inhibited the inflammation induced by carrageenan. In addition, carrageenan administration increased infiltration of inflammatory leukocytes which produce reactive oxygen species (ROS). However, the number of inflammatory leukocytes was significantly lower in the radon-treated group than in the carrageenan administrated, sham-treated mice. These findings may indicate that radon inhalation reduced ROS production induced by carrageenan administration. Furthermore, SOD and catalase activities in paws were significantly higher in the carrageenan administrated, radon-treated mice than in the carrageenan administrated, sham-treated mice. These findings indicated that radon inhalation had anti-inflammatory effects and inhibited carrageenan-induced inflammatory paw edema.

References:
Takahiro Kataoka, Junichi Teraoka, Akihiro Sakoda, Yuichi Nishiyama, Keiko Yamato, Mayuko Monden, Yuu Ishimori, Takaharu Nomura, Takehito Taguchi, and Kiyonori Yamaoka. Protective Effects of Radon Inhalation on Carrageenan-Induced Inflammatory Paw Edema in Mice. 
Inflammation Vol. 35, No. 2, 713-722 (2012) 

Apr 01, 2012

Takahiro KATAOKA (Graduate School of Health Sciences, Okayama University)

Adequate oxygen stress induced by low-dose irradiation activates biodefense system, such as induction of the synthesis of superoxide dismutase (SOD) and glutathione peroxidase.We studied the possibility for alleviation of oxidative damage, such as diabetes and nonalcoholic liver disease. Results show that low-dose γ-irradiation increases SOD activity and protects against alloxan diabetes. Prior or post-low-dose X- or γ-irradiation increases antioxidative functions in livers and inhibits ferric nitrilotriacetate and carbon tetrachloride-induced (CCl4) hepatopathy. Moreover, radon inhalation also inhibits CCl4-induced hepatopathy. It is highly possible that low-dose irradiation including radon inhalation activates the biodefence systems and, therefore, contributes to preventing or reducing reactive oxygen species-related diabetes and nonalcoholic liver disease, which are thought to involve peroxidation.

References:
Takahiro Kataoka, Kiyonori Yamaoka. Activation of Biodefense System by Low-Dose Irradiation or Radon Inhalation and Its Applicable Possibility for Treatment of Diabetes and Hepatopathy 
ISRN Endocrinology (2012) Vol. 2012, Article ID 292041, 11 pages 
doi:10.5402/2012/292041

Apr 26, 2012

Takahiro KATAOKA (Graduate School of Health Sciences, Okayama University)

Aug 27, 2011.
Takahiro KATAOKA (Graduate School of Health Sciences, Okayama University)

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Therapy involving radon gas volatilized from radon-enriched water is performed for various diseases at Misasa Medical Center, Okayama University Hospital. Although hepatic and renal damage are not the main indication for radon therapy, our previous report suggested that radon inhalation may mitigate liver and kidney damage. In this study, we assessed whether radon inhalation provided protection from carbon tetrachloride (CCl4)-induced hepatic and renal damage in mice. Mice were subjected to intraperitoneal injection of CCl4 after inhaling approximately 18 kBq/m3 radon for 6 h. Radon inhalation significantly increased total glutathione (t-GSH) content and glutathione peroxidase (GPx) activity in the liver and kidney. Injection of CCl4 was associated with significantly higher levels of glutamic oxaloacetic transaminase (GOT) and alkaline phosphatase (ALP) activity and creatinine level in serum, and pretreatment with radon significantly decreased the GOT and ALP activity and creatinine level associated with CCl4 injection, suggesting that radon inhalation alleviates CCl4-induced hepatic and renal damage. The t-GSH contents and GPx activity in the liver and kidney of animals pretreated with radon were significantly higher than those of the CCl4-only group. These findings suggested that radon inhalation activated antioxidative functions and inhibited CCl4-induced hepatic and renal damage in mice. Although some reports suggested that low-dose X-irradiation inhibited liver damage, it can be estimated that the effective dose of radon is considerably smaller than that of X-irradiation. Therefore, these findings suggest the possibility of a new therapy to treat liver and kidney damage.

References:
Takahiro Kataoka, Yuichi Nishiyama, Teruaki Toyota, Masaaki Yoshimoto, Akihiro Sakoda, Yuu Ishimori, Yutaka Aoyama, Takehito Taguchi, and Kiyonori Yamaoka. Radon Inhalation Protects Mice from Carbon-Tetrachloride-Induced Hepatic and Renal Damage
Inflammation (2011), Vol. 34, No. 6, pp. 559–567

Aug 07, 2011

Takahiro KATAOKA (Graduate School of Health Sciences, Okayama University)

Exposure to radon activates antioxidative functions in mouse and rat. However, dose–dependent or dose rate–dependent changes in antioxidative functions in organs exposed to radon are still unknown. The purpose of this study was to investigate the response of plasma, brain, lung, thymus, heart, liver, stomach, pancreas, kidney, and small intestine to radon. In this study, we examined changes of superoxide dismutase (SOD) activity using a new large-scale facility for exposing small animals to radon. Mice were exposed to radon at a concentration of 250, 500, 1000, 2000, or 4000 Bq/m3 for 0.5, 1, 2, 4, or 8 days. When mice were exposed to radon at 2000 day•Bq/m3, activation of SOD activities in plasma, liver, pancreas, heart, thymus, and kidney showed dose–rate effects. Our results also suggested that continuous exposure to radon increased SOD activity, but SOD activity transiently returned to normal levels at around 2 days. Moreover, we classified the organs into four groups (1. plasma, brain, lung; 2. heart, liver, pancreas, small intestine; 3. kidney, thymus; 4. stomach) based on changes in SOD activity. Thymus had the highest responsiveness and stomach had lowest. The radon therapy is used to meet the indications of lifestyle diseases, such as arteriosclerosis, osteoarthritis, bronchial asthma, and emphysema. Our data suggested some new indications for radon treatment. Specifically, it is highly possible that radon inhalation inhibits brain disorder induced by reactive oxygen species.

References:
Takahiro Kataoka, Akihiro Sakoda, Yuu Ishimori, Teruaki Toyota, Yuichi Nishiyama, Hiroshi Tanaka, Fumihiro Mitsunobu, Kiyonori Yamaoka. Study of the response of superoxide dismutase in mouse organs to radon using a new large-scale facility for exposing small animals to radon.
Journal of Radiation Research (2011), Vol. 52, No. 6, pp. 775-781
doi:10.1269/jrr.10072