Combined effects of radiation and simulated microgravity on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice.

Explorations of the Moon and Mars are planned as future manned space missions, during which humans will be exposed to both radiation and microgravity. We do not, however, know the health effects for such combined exposures. In a ground-based experiment, we evaluated the combined effects of radiation and simulated microgravity on tumorigenesis by performing X-irradiation and tail suspension in C3B6F1 ApcMin/+ mice, a well-established model for intestinal tumorigenesis. Mice were irradiated at 2 weeks of age and underwent tail suspension for 3 or 11 weeks using a special device that avoids damage to the tail. The tail suspension treatment significantly reduced the thymus weight after 3 weeks but not 11 weeks, suggesting a transient stress response. The combination of irradiation and tail suspension significantly increased the number of small intestinal tumors less than 2 mm in diameter as compared with either treatment alone. The combined treatment also increased the fraction of malignant tumors among all small intestinal tumors as compared with the radiation-only treatment. Thus, the C3B6F1 ApcMin/+ mouse is a useful model for assessing cancer risk in a simulated space environment, in which simulated microgravity accelerates tumor progression when combined with radiation exposure.

Radiation inducible MafB gene is required for thymic regeneration.

The thymus facilitates mature T cell production by providing a suitable stromal microenvironment. This microenvironment is impaired by radiation and aging which lead to immune system disturbances known as thymic involution. Young adult thymus shows thymic recovery after such involution. Although various genes have been reported for thymocytes and thymic epithelial cells in such processes, the roles of stromal transcription factors in these remain incompletely understood. MafB (v-maf musculoaponeurotic fibrosarcoma oncogene homolog B) is a transcription factor expressed in thymic stroma and its expression was induced a day after radiation exposure. Hence, the roles of mesenchymal MafB in the process of thymic regeneration offers an intriguing research topic also for radiation biology. The current study investigated whether MafB plays roles in the adult thymus. MafB/green fluorescent protein knock-in mutant (MafB+/GFP) mice showed impaired thymic regeneration after the sublethal irradiation, judged by reduced thymus size, total thymocyte number and medullary complexity. Furthermore, IL4 was induced after irradiation and such induction was reduced in mutant mice. The mutants also displayed signs of accelerated age-related thymic involution. Altogether, these results suggest possible functions of MafB in the processes of thymic recovery after irradiation, and maintenance during aging.

Simultaneous exposure to chronic irradiation and simulated microgravity differentially alters immune cell phenotype in mouse thymus and spleen.

Deep-space missions may alter immune cell phenotype in the primary (e.g., thymus) and secondary (e.g., spleen) lymphoid organs contributing to the progression of a variety of diseases. In deep space missions, astronauts will be exposed to chronic low doses of HZE radiation while being in microgravity. Ground-based models of long-term uninterrupted exposures to HZE radiation are not yet available. To obtain insight in the effects of concurrent exposure to microgravity and chronic irradiation (CIR), mice received a cumulative dose of chronic 0.5 Gy gamma rays over one month ± simulated microgravity (SMG). To obtain insight in a dose rate effect, additional mice were exposed to single acute irradiation (AIR) at 0.5 Gy gamma rays. We measured proportions of immune cells relative to total number of live cells in the thymus and spleen, stress level markers in plasma, and change in body weight, food consumption, and water intake. CIR affected thymic CD3+/CD335+ natural killer T (NK-T) cells, CD25+ regulatory T (Treg) cells, CD27+/CD335- natural killer (NK1) cells and CD11c+/CD11b- dendritic cells (DCs) differently in mice subjected to SMG than in mice with normal loading. No such effects of CIR on SMG as compared to normal loading were observed in cell types from the spleen. Differences between CIR and AIR groups (both under normal loading) were found in thymic Treg and DCs. Food consumption, water intake, and body weight were less after coexposure than singular or no exposure. Compared to sham, all treatment groups exhibited elevated plasma levels of the stress marker catecholamines. These data suggest that microgravity and chronic irradiation may interact with each other to alter immune cell phenotypes in an organ-specific manner and appropriate strategies are required to reduce the health risk of crewmembers.

Gender differences in UV-induced skin inflammation, skin carcinogenesis and systemic damage.

Ultraviolet (UV) radiation-induced chronic inflammation contributes to all stages of skin tumor development. In addition, gender plays an important role in inflammatory diseases or cancer. In this study, histopathology changes, hematology, oxidative stress and inflammatory response were used to evaluate sex differences in UV-induced chronic inflammation-associated cancer development. The results showed that the male and female mice had photoaging damage at the 9th week. However, skin tumors only appeared in male mice at 31st week. Furthermore, UV increased ROS production, p65, p-p65, IL-6 and TNF-α protein expressions in skin, and these factors elevated more in male mouse model. Hematology results showed that the parameters of blood systemic inflammation were changed in different degrees in model groups, while the pathological results showed inflammatory cell infiltration in the internal organs of both model groups in varying degrees. These results indicate that there are gender differences in UV-induced skin inflammation, carcinogenesis and systemic damage. Moreover, male mice are more sensitive to UV irradiation, which may be responsible to greater oxidative stress and inflammatory damage.

Immune Reconstitution and Thymic Involution in the Acute and Delayed Hematopoietic Radiation Syndromes.

Lymphoid lineage recovery and involution after exposure to potentially lethal doses of ionizing radiation have not been well defined, especially the long-term effects in aged survivors and with regard to male/female differences. To examine these questions, male and female C57BL/6 mice were exposed to lethal radiation at 12 wk of age in a model of the Hematopoietic-Acute Radiation Syndrome, and bone marrow, thymus, spleen, and peripheral blood examined up to 24 mo of age for the lymphopoietic delayed effects of acute radiation exposure. Aged mice showed myeloid skewing and incomplete lymphocyte recovery in all lymphoid tissues. Spleen and peripheral blood both exhibited a monophasic recovery pattern, while thymus demonstrated a biphasic pattern. Naïve T cells in blood and spleen and all subsets of thymocytes were decreased in aged irradiated mice compared to age-matched non-irradiated controls. Of interest, irradiated males experienced significantly improved reconstitution of thymocyte subsets and peripheral blood elements compared to females. Bone marrow from aged irradiated survivors was significantly deficient in the primitive lymphoid-primed multipotent progenitors and common lymphoid progenitors, which were only 8-10% of levels in aged-matched non-irradiated controls. Taken together, these analyses define significant age- and sex-related deficiencies at all levels of lymphopoiesis throughout the lifespan of survivors of the Hematopoietic-Acute Radiation Syndrome and may provide a murine model suitable for assessing the efficacy of potential medical countermeasures and therapeutic strategies to alleviate the severe immune suppression that occurs after radiation exposure.

Flavonoids from Rosaroxburghii Tratt prevent reactive oxygen species-mediated DNA damage in thymus cells both combined with and without PARP-1 expression after exposure to radiation in vivo.

This study aimed to evaluate the role of FRT in ROS/DNA regulation with or without PARP-1 in radiation-injured thymus cells. The administration of FRT to PARP-1-/- (KO) mice demonstrated that FRT significantly increased the viability of thymus cells and decreased their rate of apoptosis through PARP-1. Radiation increased the levels of ROS, γ-H2AX and 53BP1, and induced DNA double strand breaks. Compared with wild type (WT) mice, levels of ROS, γ-H2AX and 53BP1 in KO mice were much less elevated. The FRT treatment groups also showed little reduction in these indicators in KO mice compared with WT mice. The results of the KO mice study indicated that FRT reduced ROS activation through inhibition of PARP-1. Furthermore, FRT reduced the concentrations of γ-H2AX by decreasing ROS activation. However, we found that FRT did not regulate 53BP1, a marker of DNA damage, because of its elimination of ROS. Levels of apoptosis-inducing factor (AIF), exhibited no significant difference after irradiation in KO mice. To summarize, ROS suppression by PARP-1 knockout in KO mice highlights potential therapeutic target either by PARP-1 inhibition combined with radiation or by treatment with a drug therapy alone. AIF-induced apoptosis could not be activated in KO mice.

Janus kinase inhibitor ruxolitinib blocks thymic regeneration after acute thymus injury.

Thymic epithelial cells (TECs) are crucial for the production of T-cells. Cancer therapies including cytotoxic drugs and ionizing radiations damage TECs resulting in abnormal T-cell production and function. Fortunately, TECs can regenerate after injury. The Janus kinase (Jak) pathway is important in supporting survival of TECs. Jak inhibitors are used to treat cancer and immune disorders. The impact of Jak inhibitors on recovery of TECs is unknown. We induced acute thymus injury in mice by using ionizing radiation and evaluated the impact of ruxolitinib on thymus regeneration. We also tested if ruxolitinib affected proliferation of TECs in vitro. An increase was observed in the recovery of thymus cells after acute injury in association with up-regulation of TEC-related growth factors including keratinocyte growth factor (Kgf), epidermal growth factor (Egf), insulin-like growth factor 1 (Igf1) and receptor activator of NF-κB ligand (Rankl). Giving ruxolitinib decreased levels of receptors of these growth factors on TECs and blocked growth factor-induced recovery of thymus cells in damaged thymii. Ruxolitinib also blocked growth factors-induced proliferation of TECs in vitro. Thymus regeneration was inhibited when ruxolitinib was given immediately after thymus injury but not when it was given 1 week later. These data may have implications for how ruxolitinib is used in clinical practices.

Quantitative analysis reveals reciprocal regulations underlying recovery dynamics of thymocytes and thymic environment in mice.

Thymic crosstalk, a set of reciprocal regulations between thymocytes and the thymic environment, is relevant for orchestrating appropriate thymocyte development as well as thymic recovery from various exogenous insults. In this work, interactions shaping thymic crosstalk and the resultant dynamics of thymocytes and thymic epithelial cells are inferred based on quantitative analysis and modeling of the recovery dynamics induced by irradiation. The analysis identifies regulatory interactions consistent with known molecular evidence and reveals their dynamic roles in the recovery process. Moreover, the analysis also predicts, and a subsequent experiment verifies, a previously unrecognized regulation of CD4+CD8+ double positive thymocytes which temporarily increases their proliferation rate upon the decrease in their population size. Our model establishes a pivotal step towards the dynamic understanding of thymic crosstalk as a regulatory network system.

1,4-Dithiothreitol treatment ameliorates hematopoietic and intestinal injury in irradiated mice: Potential application of a treatment for acute radiation syndrome.

Radiation exposure poses a significant threat to public health, which can lead to acute hematopoietic system and intestinal system injuries due to their higher radiation sensitivity. Hence, antioxidants and thiol-reducing agents could have a potential protective effect against this complication. The dithiol compound 1,4-dithiothreitol (DTT) has been used in biochemistry, peptide/protein chemistry and clinical medicine. However, the effect of DTT on ionizing radiation (IR)-induced hematopoietic injury and intestinal injury are unknown. The current investigation was designed to evaluate the effect of DTT as a safe and clinically applicable thiol-radioprotector in irradiated mice. DTT treatment improved the survival of irradiated mice and ameliorated whole body irradiation (WBI)-induced hematopoietic injury by attenuating myelosuppression and myeloid skewing, increasing self-renewal and differentiation of hematopoietic progenitor cells/hematopoietic stem cells (HPCs/HSCs). In addition, DTT treatment protected mice from abdominal irradiation (ABI)-induced changes in crypt-villus structures and function. Furthermore, treatment with DTT significantly enhanced the ABI-induced reduction in Olfm4 positive cells and offspring cells of Lgr5+ stem cells, including lysozyme+ Paneth cells and Ki67+ cells. Moreover, IR-induced DNA strand break damage, and the expression of proapoptotic-p53, Bax, Bak protein and antiapoptotic-Bcl-2 protein were reversed in DTT treated mice, and DTT also promoted small intestine repair after radiation exposure via the p53 intrinsic apoptotic pathway. In general, these results demonstrated the potential of DTT for protection against hematopoietic injury and intestinal injury after radiation exposure, suggesting DTT as a novel effective agent for radioprotection.

[Metabolic and ultrastructural adaptation mechanisms during the primary prophylactic action of low-intensity electromagnetic radiation under normal and radiation conditions]. / Metabolicheskie i ul'trastrukturnye mekhanizmy adaptatsii pri pervichno-profilakticheskom deistvii nizkointensivnogo élektromagnitnogo izlucheniia v usloviiakh normy i radiatsii.

BACKGROUND: Experimental studies have established that that low-intensity ultrahigh frequency (UHF) electromagnetic radiation (EMR) has a preventive effect under the action of radiation and other pathogenic factors, which manifests itself in the accelerated development of adaptation, in the predominance of anabolic reactions over catabolic ones, and in the strengthening of the body' structural reserves. At the same time, from the standpoint of studying the mechanisms of primary prevention, it is very important not only to identify the overall adaptation effect, but also to have an idea on the specific contribution of a physical factor used in the development of adaptation. AIM: To identify metabolic and ultrastructural adaption parameters under the action of low-intensity UHF EMR on healthy animals and to determine their stability (safety), by using a model of radiation exposure. MATERIAL AND METHODS: The experiments were carried on 42 mature male rats weighing 180-200g. All the rats were divided into 5 groups: 2 experimental groups of 8 animals each for the comparative study of the specific features of adaptation developed under the preliminary action of UHF EMR in healthy animals and under radiation; 2 control groups of 8 animals each, and one intact group of 10 animals. The lumbar region (the area of the projection of the adrenal glands) was exposed to UHF EMP for 2 min daily (a cycle of 10 sessions). The animals were once irradiated at 2 Gy 60Co gamma ray doses, by using an Agat-R apparatus. The investigation objects were the liver, adrenal glands, testes, and thymus. The investigators used biochemical assays (the levels of RNA and DNA, antioxidant activity, specific activity in the thymocyte genome), transmission electron microscopy of adrenocorticocytes in the adrenal bundle zone and Sertoli cells in the testis. Mitochondria (number, average and total area, number of cristae) were morphometrically analyzed. RESULTS: The metabolic and ultrastructural adaption changes induced by UHF EMR in healthy animals were ascertained to be able to withstand the pathogenic effect of radiation and at the same time showed both stability (safety) and certain variability (plasticity) in their reactions. In this case, there were increases in the synthesis of nucleic acids and in the activity of the antioxidant system; there was also mitochondrial structural stability that was more manifested in the adrenocorticocytes in the adrenal bundle zone. At the same time, there was also a decrease in the intensity (magnitude) of a number of adaptive indicators, although by and large they were significantly higher than the level of control (the effect of radiation). DISCUSSION: Thus, the effect of UHF EMR on healthy animals contributed to the development of adaptive rearrangements in the organs studied. The essence of these changes was mainly the enhancement of synthetic reactions, as indicated by a larger amount of RNA and DNA, the activation of cellular and intracellular regeneration with the increased processes of hyperplasia of the mitochondrial cristae and the higher levels of ribosomes and polysomes. In addition, it can be assumed that the use of UHF EMR has laid the physicochemical foundations of its antioxidant action as conformational rearrangements in the membranes, which increased their structural stability. The findings are indicative of the increased level of morphofunctional reserves in the studied cells and tissues due to their increased bioenergetic and plastic potential. CONCLUSION: This study has provided new data that expand our understanding of the features of the development of adaptive mechanisms and the formation of the body's structural and functional reserves under the primary prophylactic action of low-intensity UHF EMR, by using the model of radiation exposure.

The effects of extremely low-frequency electromagnetic fields on c-Maf, STAT6, and RORα expressions in spleen and thymus of rat.

The study investigated the effect of extremely low-frequency electromagnetic fields (ELF-EMFs) exposure at different magnetic flux densities on genes expression of transcription factor Maf (c-Maf), signal transducer and activator of transcription 6 (STAT6), and retinoid-related orphan receptor alpha (RORα) in the spleen and thymus of rats. Eighty adult male rats were separated into four ELF-EMFs exposed and were exposed to magnetic flux densities of 1, 100, 500, and 2000 µT at a frequency of 50 Hz for 2 h daily for up to 60 d. All rats were intraperitoneally immunized on d 31, 44, and 58 of exposure. The experimental results showed that the expression levels of c-Maf, STAT6, and RORα in the thymus were not significantly changed at different magnetic flux densities. The expression levels of RORα and c-Maf were significantly downregulated at the densities of 1 and 100 µT, while the expression of STAT6 was only significantly decreased at the density of 100 µT. In conclusion, low magnetic flux densities of ELF-EMFs may reduce the expression levels of c-Maf, STAT6, and RORα genes in the spleen.

Fatty Acid Content and Tumor Growth Changes in Mice After Exposure to Extremely High-Frequency Electromagnetic Radiation and Consumption of N-3 Fatty Acids.

The topical problem is to find new, more effective and safe treatments for cancer. The purpose of the present work was to study the combined effects of low-intensity extremely high-frequency electromagnetic radiation (EHF EMR) and consumption of n-3 polyunsaturated fatty acids (PUFAs) on tumor growth and the content of FAs in the thymus and tumor tissue in mice. Fatty acid composition was determined using gas chromatography. Exposure of tumor-bearing mice with solid Ehrlich carcinoma to EHF EMR with effective parameters (42.2 GHz, 0.1 mW/cm2, 20 min daily for 5 consecutive days beginning on the first day after the tumor inoculation) led to delaying the tumor growth and restored the content of almost all FAs in thymic tissue to the level of intact animals. Animal intake of the preparation enriched with n-3 PUFAs increased the content of n-3 PUFAs in thymic tissue significantly, but did not affect the tumor growth, even in combination with EHF EMR exposure. Combined action of EHF EMR exposure and n-3 preparation promoted recovery of thymus weight in tumor-bearing animals. The data obtained assume a complex interaction between the immune system and the tumor, and the important role of FAs in the regulation of this interaction.

A small fish model for quantitative analysis of radiation effects using visualized thymus responses in GFP transgenic medaka.

Purpose: The aim of this study was to establish a new method of real-time, in vivo detection of radiation damage and recovery. Methods: The thymus was observed under fluorescent light in a green fluorescent protein transgenic medaka. After irradiation, medaka thymus images were analyzed to quantify the effects of radiation by measuring changes in thymus size. A single acute irradiation of X-rays (0-30 Gy) or heavy Fe ions (0-10 Gy) was delivered to the medaka. Images were captured 0, 1, 2, 3, 5, 7, 11, and 21 d after irradiation. Dose-response assessment was conducted to provide a direct measurement of the effects of the radiation. Conclusion: A biomonitoring system to detect the effects of radiation in real time was established. Using this system, the threshold doses for the induction of thymic atrophy by acute X-rays and Fe ions were 2-5 Gy and 0.5-1 Gy, respectively. The Relative Biological Effectiveness (RBE) of Fe-ion to X-rays was estimated to be around 3. This system may be used to evaluate the risk from concurrent exposure to hazards, such as chemicals and radiation, and for aging research.

p53 ß-hydroxybutyrylation attenuates p53 activity.

p53 is an essential tumor suppressor, whose activity is finely tuned by the posttranslational modifications. Previous research has reported that ß-hydroxybutyrate (BHB) induces ß-hydroxybutyrylation (Kbhb), which is a novel histone posttranslational modification. Here we report that p53 is modified by kbhb and that this modification occurs at lysines 120, 319, and 370 of p53. We demonstrate that the level of p53 kbhb is dramatically increased in cultured cells treated with BHB and in thymus tissues of fasted mice, and that CBP catalyze p53 kbhb. We show that p53 kbhb results in lower levels of p53 acetylation and reduced expression of the p53 downstream genes p21 and PUMA, as well as reduced cell growth arrest and apoptosis in cultured cells under p53-activating conditions. Similar results were observed in mouse thymus tissue under starvation conditions, which result in increased concentrations of serum BHB, and in response to genotoxic stress caused by γ-irradiation to activate p53. Our findings thus show that BHB-mediated p53 kbhb is a novel mechanism of p53 activity regulation, which may explain the link between ketone bodies and tumor, and which may provide promising therapeutic target for cancer treatment.

Late effects of total body irradiation on hematopoietic recovery and immune function in rhesus macaques.

While exposure to radiation can be lifesaving in certain settings, it can also potentially result in long-lasting adverse effects, particularly to hematopoietic and immune cells. This study investigated hematopoietic recovery and immune function in rhesus macaques Cross-sectionally (at a single time point) 2 to 5 years after exposure to a single large dose (6.5 to 8.4 Gray) of total body radiation (TBI) derived from linear accelerator-derived photons (2 MeV, 80 cGy/minute) or Cobalt 60-derived gamma irradiation (60 cGy/min). Hematopoietic recovery was assessed through measurement of complete blood counts, lymphocyte subpopulation analysis, and thymus function assessment. Capacity to mount specific antibody responses against rabies, Streptococcus pneumoniae, and tetanus antigens was determined 2 years after TBI. Irradiated macaques showed increased white blood cells, decreased platelets, and decreased frequencies of peripheral blood T cells. Effects of prior radiation on production and export of new T cells by the thymus was dependent on age at the time of analysis, with evidence of interaction with radiation dose for CD8+ T cells. Irradiated and control animals mounted similar mean antibody responses to proteins from tetanus and rabies and to 10 of 11 serotype-specific pneumococcal polysaccharides. However, irradiated animals uniformly failed to make antibodies against polysaccharides from serotype 5 pneumococci, in contrast to the robust responses of non-irradiated controls. Trends toward decreased serum levels of anti-tetanus IgM and slower peak antibody responses to rabies were also observed. Taken together, these data show that dose-related changes in peripheral blood cells and immune responses to both novel and recall antigens can be detected 2 to 5 years after exposure to whole body radiation. Longer term follow-up data on this cohort and independent validation will be helpful to determine whether these changes persist or whether additional changes become evident with increasing time since radiation, particularly as animals begin to develop aging-related changes in immune function.

Kinetics of cytokine mRNA and protein expression by plastic adherent cells in the thymus after split-dose irradiation.

Whole body irradiation causes significant apoptosis in various tissues such as the thymus. If apoptotic cells outnumber the phagocytic capacity of macrophages, apoptosis becomes secondary necrosis, inducing inflammatory cytokine expression in macrophages. Radiation also induces thymic lymphomas in C57BL/6 mice after four consecutive irradiations with 1.6 Gy X-rays with nearly 100% incidence. Since cancer development is modulated by a microenvironment involving macrophages, we examined the kinetics of thymocyte number and plastic adherent cell number in the thymus as well as cytokine mRNA expression by plastic adherent cells in the thymus after split-dose irradiation. Upon split-dose irradiation, thymocyte number changed dramatically, whereas plastic adherent cell number did not. Among cytokine mRNAs tested, IL-1ß, IL-11 and IL-12p40 mRNAs were up regulated 2 days after the 1st and 2nd, 3rd and 4th, and 2nd and 3rd irradiations, respectively. On the other hand, TNF-α mRNA was up regulated 2 days after the 3rd irradiation and 2 weeks after the 4th irradiation. The level of IL-11 protein was also increased 2 days after 3rd and 4th irradiations. These results suggest that, upon split-dose irradiation, macrophages in the thymus produce various cytokines in a time-dependent manner, thereby contributing to induction of thymic lymphomas.

Regeneration After Radiation- and Immune-Mediated Tissue Injury Is Not Enhanced by Type III Interferon Signaling.

PURPOSE: Type I interferon (IFN-I) and interleukin (IL)-22 modulate regeneration of the thymus and intestinal epithelial cells (IECs) after cytotoxic stress such as irradiation. Radiation-induced damage to thymic tissues and IECs is a crucial aspect during the pathogenesis of inadequate immune reconstitution and acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative total body irradiation (TBI), respectively. IL-22 and IFN-I reduce the severity of acute GVHD after allo-HSCT with myeloablative TBI. However, the role of biologically related type III interferon (IFN-III), also known as interferon lambda (IFN-λ) or IL-28, in this context is unclear. We therefore studied the role of the IFN-III pathway in thymic regeneration and GVHD after TBI and allo-HSCT. METHODS AND MATERIALS: Cohoused wild-type (WT) and IFN-III receptor-deficient (IL-28 receptor alpha subunit-deficient/IL-28Ra-/-) mice were analyzed in models of TBI-induced thymus damage and a model of GVHD after allo-HSCT with myeloablative TBI. PASylated IFN-III (PASylated IL-28A, XL-protein GmbH) was generated to prolong the plasma half-life of IFN-III. Pharmacologic activity and the effects of PASylated IL-28A on radiation-induced thymus damage and the course of GVHD after allo-HSCT with myeloablative TBI were tested. RESULTS: The course and severity of GVHD after myeloablative TBI and allo-HSCT in IL-28Ra-/- mice was comparable to those in WT mice. Activation of the IFN-III pathway by PASylated IL-28A did not significantly modulate GVHD after allo-HSCT with TBI. Furthermore, IL28Ra-/- mice and WT mice showed similar thymus regeneration after radiation, which could also not be significantly modulated by IFN-III receptor engagement using PASylated IL-28A. CONCLUSIONS: We analyzed the role of IFN-III signaling during radiation-mediated acute tissue injury. Despite molecular and biologic homologies with IFN-I and IL-22, IFN-III signaling did not improve thymus regeneration after radiation or the course of GVHD after myeloablative TBI and allo-HSCT.

Minimal uranium accumulation in lymphoid tissues following an oral 60-day uranyl acetate exposure in male and female C57BL/6J mice.

High levels of uranium (U) exist in soil, water, and air in the Southwestern United States due, in part, to waste generated from more than 160,000 abandoned hard rock mines located in this region. As a result, many people living in this region are chronically exposed to U at levels that have been linked to detrimental health outcomes. In an effort to establish a relevant in vivo mouse model for future U immunotoxicity studies, we evaluated the tissue distribution of U in immune organs; blood, bone marrow, spleen, and thymus, as well as femur bones, kidneys, and liver, following a 60-d drinking water exposure to uranyl acetate (UA) in male and female C57BL/6J mice. Following the 60-d exposure, there was low overall tissue retention of U (<0.01%) at both the 5 and the 50 ppm (mg/L) oral concentrations. In both male and female mice, there was limited U accumulation in immune organs. U only accumulated at low concentrations in the blood and bone marrow of male mice (0.6 and 16.8 ng/g, respectively). Consistent with previous reports, the predominant sites of U accumulation were the femur bones (350.1 and 399.0 ng/g, respectively) and kidneys (134.0 and 361.3 ng/g, respectively) of male and female mice. Findings from this study provide critical insights into the distribution and retention of U in lymphoid tissues following chronic drinking water exposure to U. This information will serve as a foundation for immunotoxicological assessments of U, alone and in combination with other metals.

Effects of various radiation doses on induced T-helper cell differentiation and related cytokine secretion.

Exposure to ionizing radiation often induces T helper (Th) cell differentiation, resulting in an imbalance of Th1 and Th2 cellular subtypes, which can affect the efficacy of cancer radiotherapy. The aim of this study was to analyze differential expression of Th1, Th2 and Th3/Type 1 regulatory T cell (Tr1) subtype-related genes and cytokines in mouse thymocytes after high- and low-dose systemic radiation, using functional classification gene arrays and Elisa assays, and to explore the molecular mechanisms underlying radiation's immune effects and their relationship with Th1/Th2 immunity. We found that expression of 8 genes was upregulated after LDR, while expression of 5 genes was downregulated. After HDR, 54 genes were upregulated and 3 genes were downregulated, including genes related to Th1, Th2 and Th3/Tr1 cellular subtypes, Th1/Th2-type immune response genes and transcription factor-related genes. In the foregoing results, LDR and HDR in the thymus induced opposite patterns of expression for Th1-, Th2- and Th3-type related cytokines TGF-ß, C/EBP-ß and TNF-α. We also found that expression of Interferon-γ (IFN-γ) and Interleukin-2 (IL-2), which have a moderating effect on immune function, was upregulated after LDR. Furthermore, the secretion of negative regulatory factors Interleukin-1ß (IL-1ß), Interleukin-4 (IL-4), transforming growth factor-ß (TGF-ß) and Interleukin-21 (IL-21) was reduced after LDR, but HDR produced the opposite effect and stimulated their expression. These findings suggest that LDR may induce a Th1-type immune response, while HDR may lead to a Th2-type immune response.

Aging of lymphoid organs: Can photobiomodulation reverse age-associated thymic involution via stimulation of extrapineal melatonin synthesis and bone marrow stem cells?

Thymic atrophy and the subsequent reduction in T-cell production are the most noticeable age-related changes affecting lymphoid organs in the immune system. In fact, thymic involution has been described as "programmed aging." New therapeutic approaches, such as photobiomodulation (PBM), may reduce or reverse these changes. PBM (also known as low-level laser therapy) involves the delivery of non-thermal levels of red or near-infrared light that are absorbed by mitochondrial chromophores, in order to prevent tissue death and stimulate healing and regeneration. PBM may reverse or prevent thymic involution due to its ability to induce extrapineal melatonin biosynthesis via cyclic adenosine monophosphate (AMP) or NF-kB activation, or alternatively by stimulating bone marrow stem cells that can regenerate the thymus. This perspective puts forward a hypothesis that PBM can alter thymic involution, improve immune functioning in aged people and even extend lifespan.