Ultraviolet radiation-induced immunosuppression of delayed-type hypersensitivity in mice

Ultraviolet (UV) radiation present in sunlight plays a critical role in the initiation and promotion of nonmelanoma skin carcinogenesis and immune suppression. The immune suppressive effects of UV have been identified as a risk factor for skin cancer induction. For these reasons, scientists have focused on elucidating the mechanisms of UV-induced immune suppression to better understand the pathogenesis of skin cancer induction. A hallmark of UV-induced immune suppression is the generation of antigen-specific suppressor T cells. These suppressor cells have been shown to suppress antitumor immunity as well as other cell-mediated responses such as delayed-type hypersensitivity (DTH) reactions. Due to the excessive cost and time involved in traditional UV carcinogenic experiments, scientists have opted to use UV-induced suppression of DTH reactions as a surrogate model. DTH has been, and continues to be, a widely used assay system to measure in vivo immune function. Although somewhat unsophisticated by today's standards, this assay has great advantages because it presents a fast, inexpensive, and reliable model system to help dissect the mechanisms involved in UV-induced immune suppression. Furthermore, the murine model of DTH enables scientists to perform additional procedures, such as adoptive transfer studies with suppressor T cells, which are currently unavailable with human subjects.     

Mast cell migration from the skin to the draining lymph nodes upon ultraviolet irradiation represents a key step in the induction of immune suppression

The UV radiation in sunlight is the primary cause of skin cancer. UV is also immunosuppressive and numerous studies have shown that UV-induced immune suppression is a major risk factor for skin cancer induction. Previous studies demonstrated that dermal mast cells play a critical role in the induction of immune suppression. Mast cell-deficient mice are resistant to the immunosuppressive effects of UV radiation, and UV-induced immune suppression can be restored by injecting bone marrow-derived mast cells into the skin of mast cell- deficient mice. The exact process however, by which mast cells contribute to immune suppression, is not known. In this study, we show that one of the first steps in the induction of immune suppression is mast cell migration from the skin to the draining lymph nodes. UV exposure, in a dose-dependent manner, causes a significant increase in lymph node mast cell numbers. When GFP(+) skin was grafted onto mast cell-deficient mice, we found that GFP(+) mast cells preferentially migrated into the lymph nodes draining the skin. The mast cells migrated primarily to the B cell areas of the draining nodes. Mast cells express CXCR4(+) and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression. Our findings indicate that UV-induced mast cell migration to draining lymph nodes, mediated by CXCR4 interacting with CXCL12, represents a key early step in UV-induced immune suppression.     

Gamma radiation effects on fruits and vegetables

Several million dollars are lost in the United States each year as a result of post harvest diseases of crops. Claim costs to railroads alone in 1958 amounted to $11 million. This work demonstrates that it is possible to extend the shelf-life of fresh fruits and vegetables at room as well as at refrigeration temperatures by gamma radiation, by surface pasteurization, sprout inhibition, and also by retarding the ripening processes. The information presented should be useful to researchers, shippers, packers, and processors.     

Cenobamate: Neuroprotective Potential of a New Antiepileptic Drug

Neurochemical Research - Central nervous system (CNS) injuries annually afflict approximately 2.7 million people in United States only, inflicting costs of nearly 100 billion US dollars. The...     

Understanding the connection between platelet-activating factor,a UV-induced lipid mediator of inflammation,immune suppression and skin cancer

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome.     

The climatology of Vitamin D producing ultraviolet radiation over the United States

The US population is located in a wide range of latitudes, longitudes, and altitudes over mainland United States. Subsequently, high UV irradiants are found at southern locales, whilst in some northern areas, particularly at high latitudes, insufficient levels of ambient UV radiation to synthesize pre Vitamin D in humans are reported. This fact, coupled with the cold northern climates (resulting in high amounts of skin covered in clothing), some people may be susceptible to hypovitaminosis D. Surprisingly, hypovitaminosis D is still relatively common in developed countries such as the USA and the UK. In a large epidemiologically based study of 15,778 noninstitutionalized adult men and women living in the US, 9% had low serum 25-hydroxyvitamin D levels (15 ng/ml) [N. Engl. J. Med. 339 (1998) 12]. Further evidence of this came from recent research by McGrath [Med. Hypertens. 56 (2001) 367] who found that adults living in South East Queensland (with Queensland known as having the highest rates of skin cancer in the world) have surprisingly high rates of Vitamin D deficiency and insufficiency (8 and 23%, respectively). Therefore, hypovitaminosis D represents a serious issue for public health in both sunny and cold climates. This paper will present data on the distribution of Vitamin D forming UV over the USA using collected spectrally resolved ambient UV data from the US EPA Brewer spectrometer UV Monitoring Network. This data is obtained from the network of 21 Brewer spectrometers deployed throughout the USA, allowing for investigation of changes in Vitamin D producing UV with season and location.     

The search for new beta-cell sources

Type 1 diabetes affects an estimated 150 million people worldwide and results from an autoimmune-mediated destruction of insulin-producing beta-cells. In the United States alone more than 16 million people are affected by this disease and it is estimated that spending for diabetes management accounts for one out of every eight healthcare dollars. In this context, scientists are proposing novel therapeutic strategies that might allow a perfect glycemic control of most patients with diabetes.     

A role for inflammatory mediators in the induction of immunoregulatory B cells

UV exposure suppresses the immune response to a variety of microbial, fungal, and viral Ags. In addition, UV radiation is a complete carcinogen and the immune suppression induced by UV radiation is a major risk factor for skin cancer induction. In this study, we examined the mechanisms underlying the induction of immune suppression and tolerance induction by UV radiation. Transferring lymph nodes cells from UV-irradiated, FITC-sensitized mice into normal recipients transferred immune tolerance. Contrary to expectations, the cell responsible was an FITC(+), IL-10-secreting, CD19(+), B220(+) B cell. Because the lipid mediator of inflammation, platelet-activating factor (PAF) is released by UV-irradiated keratinocytes and is essential for the induction of immune suppression, we determined its role in tolerance induction. When UV-irradiated mice were injected with PCA 4248, a selective PAF receptor (PAFR) antagonist, transfer of tolerance was suppressed. However, immune suppression was not transferred when FITC(+) cells from the draining lymph nodes of UV-irradiated, PAFR-deficient donor mice were injected into the recipients. Because PCA 4248 also blocks serotonin receptor binding, we measured the effect that blocking both serotonin and PAFR binding has on the transfer of immune suppression. Only when both PAF and serotonin binding were blocked could we inhibit tolerance induction. These data identify a novel function for PAF and serotonin in modulating immune function, the activation of immunoregulatory B cells.     

Spinal Cord Injury: A Review of Current Therapy, Future Treatments, and Basic Science Frontiers

The incidence of acute and chronic spinal cord injury (SCI) in the United States is more than 10,000 per year, resulting in 720 cases per million persons enduring permanent disability each year. The economic impact of SCI is estimated to be more than 4 billion dollars annually. Preclinical studies, case reports, and small clinical trials suggest that early treatment may improve neurological recovery. To date, no proven therapeutic modality exists that has demonstrated a positive effect on neurological outcome. Emerging data from recent preclinical and clinical studies offer hope for this devastating condition. This review gives an overview of current basic research and clinical studies for the treatment of SCI.     

Streptococcal Superantigen,Mitogenic Factor,and Pyrogenic Exotoxin B Expressed by Streptococcus pyogenes

Abstract

Streptococcus pyogenes is a Gram-positive human bacterial pathogen that causes pharyngitis, tonsillitis, skin infections (impetigo, erysipelis, and other forms of pyoderma), acute rheumatic fever (ARF), scarlet fever (SF), poststreptococcal glomerulonephritis (PSGN), a streptococcal toxic shock syndrome (STSS), and necrotizing fasciitis. These infections are some of the most economically and medically important conditions that affect humans. For example, globally, ARF is the most common cause of pediatric heart disease. It is estimated that in India more than six million school-aged children suffer from rheumatic heart disease (1). In the United States, “sore throat” is the third most common reason for physician office visits and S. pyogenes is recovered from about 30% of children with this complaint (2). It has been estimated that there are 25–35 million cases of streptococcal pharyngitis per year in the United States, and these infections cause 1–2 billion dollars per year in direct health care costs (3,4). Although the continued great morbidity and mortality caused by S. pyogenes in developing nations, the significant health care financial burden attributable to group A streptococci in the United States, and increasing levels of antibiotic resistance (5), have highlighted the need for a fuller understanding of the molecular pathogenesis of streptococcal infection, it has been the relatively recent intercontinental increase in streptococcal disease frequency and severity (6,7) that has resulted in renewed interest in S. pyogenes virulence factors and host-parasite interactions.     

Current Estimates of the Economic Cost of Obesity in the United States

This study was undertaken to update and revise the estimate of the economic impact of obesity in the United States. A prevalence-based approach to the cost of illness was used to estimate the economic costs in 1995 dollars attributable toobesity for type 2 diabetes mellitus, coronary heart disease (CHD), hypertension, gallbladder disease, breast, endometrial and colon cancer, and osteoarthritis. Additionally and independently, excess physician visits, work-lost days, restricted activity, and bed-days attributable to obesity were analyzed cross-sectionally using the 1988 and 1994 National Health Interview Survey (NHIS). Direct (personal health care, hospital care, physician services, allied health services, and medications) and indirect costs (lost output as a result of a reduction or cessation of productivity due to morbidity or mortality) are from published reports and inflated to 1995 dollars using the medical component of the consumer price index (CPI) for direct cost and the all-items CPI for indirect cost. Population-attributable risk percents (PAR%) are estimated from large prospective studies. Excess work-lost days, restricted activity, bed-days, and physician visits are estimated from 88,262 U. S. citizens who participated in the 1988 NHIS and 80,261 who participated in the 1994 NHIS. Sample weights have been incorporated into the NHIS analyses, making these data generalizable to the U. S. population. The total cost attributable to obesity amounted to $99. 2 billion dollars in 1995. Approximately $51. 64 billion of those dollars were direct medical costs. Using the 1994 NHIS data, cost of lost productivity attributed to obesity (BMI≥30) was $3. 9 billion and reflected 39. 2 million days of lost work. In addition, 239 million restricted-activity days, 89. 5 million bed-days, and 62. 6 million physician visits were attributable to obesity in 1994. Compared with 1988 NHIS data, in 1994 the number of restricted-activity days (36%), bed-days (28%), and work-lost days (50%) increased substantially. The number of physician visits attributed to obesity increased 88% from 1988 to 1994. The economic and personal health costs of overweight and obesity are enormous and compromise the health of the United States. The direct costs associated with obesity represent 5. 7% of our National Health Expenditure in the United States .     

Economic Aspects of “Whiplash” Injury

The term “whiplash,” used to describe a neck injury received in an automobile accident, has no foundation in medical science to support the complaints of persons suing for damages. The term is gaining unwarranted popularity as a term describing an injury, even though there are no clinical or pathological findings to support it.“Whiplash” cases today account for an estimated 30 per cent of all injuries in automobile accidents. Direct compensation for damages paid to persons injured in automobile accidents in the United States in 1961 amounted to approximately one billion, seven hundred million dollars. It has been estimated that five hundred and eighty million dollars of that amount was paid in compensation on allegation of neck injuries.     

IL-12 prevents the inhibitory effects of cis-urocanic acid on tumor antigen presentation by Langerhans cells: implications for photocarcinogenesis.

UV radiation induces skin cancer primarily by its DNA-damaging properties, but also by its capacity to suppress the immune system. The photoisomer of urocanic acid (UCA), cis-UCA, is an important mediator of UV-induced immunosuppression and is involved in the inhibition of tumor immunity. The immunomodulatory cytokine IL-12 is known to counteract many of the immunosuppressive effects of UV radiation, including UV-induced immune tolerance. In this study, we addressed whether IL-12 also reverts the immunosuppressive activities of cis-UCA. Cis-UCA inhibits the ability of Langerhans cells to present tumor Ags for primary and secondary tumor immune responses. IL-12 treatment completely prevented the suppression by cis-UCA. IL-12 also protected mice from cis-UCA-induced suppression of contact hypersensitivity responses. To study the effects of cis-UCA on Ag-processing and Ag-presenting function in vitro, Langerhans cells were treated with UCA isomers and incubated with OVA or OVA peptide(323-339) before exposure to OVA-specific transgenic T cells. Cis-, but not trans-UCA suppressed Ag presentation, which was completely reversed upon addition of IL-12. Since these findings suggest that cis-UCA may play an important role in photocarcinogenesis by inhibiting a tumor immune response, mice were chronically UVB irradiated to induce skin cancer. Whereas all mice in the control groups developed tumors, mice treated with a mAb with specificity for cis-UCA showed a significantly reduced tumor incidence. These data strongly indicate the importance of cis-UCA during photocarcinogenesis and support the concept of counteracting cis-UCA as an alternative strategy to prevent UV-induced skin cancer, possibly via the application of IL-12.     

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

Skin cancer is the most common cancer in the United States and is mainly caused by environmental UV radiation. Reducing skin cancer incidence is becoming an urgent issue. The stress-inducible protein Sestrin2 (Sesn2) plays an important role in maintaining redox and metabolic homeostasis and their related pathologies. However, the role of Sesn2 in cancer remains unclear. Here we show that UVB radiation induces Sesn2 expression in normal human keratinocytes, mouse skin, normal human melanocytes, and melanoma cells. In addition, Sesn2 promotes AKT activation through a PTEN-dependent mechanism. Sesn2 deletion or knockdown sensitizes squamous cell carcinoma (SCC) cells to 5-fluorouracil-induced apoptosis and melanoma cells to UVB- and vemurafenib-induced apoptosis. In mice Sesn2 knockdown suppresses tumor growth from injected human SCC and melanoma cells. Last, as compared with normal skin, Sesn2 is up-regulated in both human skin SCC and melanoma. Our findings demonstrate that Sesn2 promotes AKT activation and survival in response to UVB stress and chemotherapeutics and suggest that Sesn2 is oncogenic in skin SCC and melanoma.     

Benefit Cost Analysis of Three Skin Cancer Public Education Mass-Media Campaigns Implemented in New South Wales,Australia

Public education mass media campaigns are an important intervention for influencing behaviour modifications. However, evidence on the effectiveness of such campaigns to encourage the population to reduce sun exposure is limited. This study investigates the benefits and costs of three skin cancer campaigns implemented in New South Wales from 2006–2013. This analysis uses Australian dollars (AUD) and 2010–11 as the currency and base year, respectively. Historical data on skin cancer were used to project skin cancer rates for the period 2006–2020. The expected number of skin cancer cases is derived by combining skin cancer rates, sunburn rates and relative risk of skin cancers due to sun exposure. Counterfactual estimates are based on sunburn exposure in the absence of the campaigns. Monetary values are attached to direct (treatment) and indirect (productivity) costs saved due to fewer skin cancer cases. Monetary benefits are compared with the cost of implementing the campaigns and are presented in the form of a benefit-cost ratio. Relative to the counterfactual (i.e., no campaigns) there are an estimated 13,174 fewer skin cancers and 112 averted deaths over the period 2006–2013. The net present value of these benefits is $60.17 million and the campaign cost is $15.63 million. The benefit cost ratio is 3.85, suggesting that for every $1 invested a return of $3.85 is achieved. Skin cancer public education mass media campaigns are a good investment given the likely extent to which they reduce the morbidity, mortality and economic burden of skin cancer.     

Climate change and human skin cancer.

As part of an inventory of potential interactions between effects of ozone depletion and climate change, a possible effect of ambient temperature on sun-induced skin cancers was suggested. Mouse experiments had shown that increased room temperature enhanced ultraviolet (UV) radiation-induced carcinogenesis; the effective UV dose was increased by 3-7% per degrees C. The present investigation was aimed at studying a possible temperature effect on human skin cancer. Existing data on the incidence of human skin cancer were analyzed, as available from two special surveys of non-melanoma skin cancer in the United States. The incidence of non-melanoma skin cancer in the ten regions surveyed not only correlated significantly with the ambient UV dose but also with the average daily maximum temperature in summer. For squamous cell carcinoma the incidence was higher by 5.5% (SE 1.6%) per degrees C and for basal cell carcinoma by 2.9% (SE 1.4%) per degrees C. These values correspond to an increase of the effective UV dose by about 2% per degrees C. Although the precise nature of this correlation with temperature requires further studies, it can be concluded that the temperature rises coming with climate change can indeed amplify the induction of non-melanoma skin cancers by UV radiation in human populations.     

Molecular mechanisms of ultraviolet radiation-induced immunosuppression

Solar ultraviolet radiation (UVR) is well known for its immunosuppressive properties. UVR can suppress immune reactions both in a local and a systemic fashion. One of the major molecular mediators of photoimmunosuppression is UVR-induced DNA damage. In contrast to immunosuppressive drugs, UVR does not act in a general but antigen-specific fashion. This is due to the induction of regulatory T cells. Epidermal Langerhans cells harboring UVR-induced DNA damage appear to be essentially involved in the induction of these cells. Cytokines including interleukin (IL)-12, -18 and -23 exert the capacity to reduce UVR-induced DNA damage via induction of DNA repair. Accordingly, these cytokines prevent UVR-mediated immunosuppression. In contrast to IL-18, IL-12 and IL-23 can also inhibit the suppressive activity of regulatory T cells by a mechanism which still needs to be determined. Clarification of the molecular mechanisms underlying UVR-induced immunosuppression will help to develop new immunosuppressive therapeutic strategies by utilizing UVR-induced regulatory T cells for the treatment of immune-mediated diseases. In addition, these insights will contribute to a better understanding of photocarcinogenesis since suppression of the immune system by UVR essentially contributes to the induction of skin cancer.     

Altitude, radiation, and mortality from cancer and heart disease

The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.     

Parameters of protection against ultraviolet radiation‐induced skin cell damage

Epidemiological and experimental evidence has supported the notion that solar ultraviolet (UV) radiation is the leading cause of skin cell damage and skin cancer. Non‐melanoma skin cancer, one of the malignancies with the most rapidly increasing incidence, is suggested to be directly related to the total exposure to solar UV light. Over the past few years, the mechanisms of cellular responses to UV radiation have received unprecedented attention. Understanding how skin cells respond to UV radiation will undoubtedly help decipher what goes wrong in a variety of clinical skin disorders including skin cancer and will facilitate the development of novel therapeutic strategies. In the past decade, studies have established that UV radiation induces multifarious signal transduction pathways, some of which lead to apoptotic cell death, while others protect against this process. In this review, we summarize some of the most recent progresses regarding the involvement of multiple signal pathways in UV radiation‐induced apoptosis in skin cells, especially in keratinocytes. These pathways include pro‐apoptosis components such as MAPK, AMPK, and p53 as well as pro‐survival components, namely, AKT and mTORC complexes. J. Cell. Physiol. 220: 277–284, 2009. © 2009 Wiley‐Liss, Inc.