Radiation-induced Immune Suppression Research Articles

Vitamin D-fence

The role of vitamin D in the immune system is complex. Vitamin D is produced in the skin following exposure to ultraviolet radiation. There is compelling evidence that vitamin D compounds protect against ultraviolet radiation-induced DNA damage and immune suppression, suggesting it may be beneficial as a skin cancer preventive agent. However, vitamin D has many modulatory effects on the immune system and it has in fact been suggested that the immune suppression generally attributed to the UVB portion of sunlight is mediated through vitamin D. Here we describe the role of vitamin D compounds as "defence" molecules against UVR-induced damage, and investigate both sides of the "fence" regarding the effects of vitamin D compounds and the immune system.

Reactive Oxygen Species in HaCaT Keratinocytes After UVB Irradiation Are Triggered by Intracellular Ca2+ Levels

It is recognized that reactive oxygen species (ROS) are responsible for skin damage due to UVB-radiation (UVB-R). However, the triggering substance(s) for ROS generation after UVB-R is uncertain with respect to the activation of NADPH oxidase (Nox), xanthine oxidase (XOD), and respiratory chain-chain reactions in mitochondria. As a first step in identifying the trigger(s) for UVB-induced ROS generation, we examined the relationship between Ca(2+) levels and ROS generation in HaCaT keratinocytes. UVB-R exposure of HaCaT keratinocytes resulted in an immediate elevation of ROS that recurred 7 hours later. This was accompanied by immediately elevated intracellular Ca(2+) . A Ca(2+) chelating agent, BAPTA, abolished the elevation of ROS after UVB-R completely. In addition, exogenous H(2)O(2) did not increase intracellular Ca(2+) levels. This suggests that intracellular Ca(2+) is the first trigger for UVB-induced ROS generation.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 50-52; doi:10.1038/jidsymp.2009.12.

Polypodium leucotomos inhibits ultraviolet B radiation‐induced immunosuppression

An extract of the tropical fern Polypodium leucotomos (PL) administered orally to mice inhibits ultraviolet B (UVB) radiation-induced skin cancer formation. UVB-induced murine skin cancers occur, in part, because of UVB-induced immunosuppression. Thus, we examined whether PL inhibits UVB-suppression of the induction of contact hypersensitivity (CHS) locally or systemically. C57BL/6 mice received standard drinking water or water-containing PL. In the local model, mice were shaved on the dorsum and exposed to 3500 J/m(2) of UVB radiation daily for 4 days. Control mice were not irradiated. After the last irradiation they were sensitized to oxazolone topically at the irradiated site. To examine the ability of PL to inhibit systemic UVB-induced immunosuppression, mice were given 10,000 J/m(2) of UVB radiation once and immunized at a non-exposed site 3 days later. Six days after immunization (in both models), mice were challenged on the ears with oxazolone and 24/48 h ear swelling assessed. PL in drinking water significantly reduced the inhibition of CHS observed with exposure to UVB radiation in both the local and systemic models. The ability of PL to inhibit UVB radiation-induced immune suppression may explain, in part, its ability to inhibit UVR-induced skin cancer induction in mice.

The Effect of a Vitamin A Acetate Diet on Ultraviolet Radiation-induced Immune Suppression as Measured by Contact Hypersensitivity in Mice†¶

The Effect of a Vitamin A Acetate Diet on Ultraviolet Radiation-induced Immune Suppression as Measured by Contact Hypersensitivity in Mice†¶

UV-induced immune suppression and photocarcinogenesis: Chemoprevention by dietary botanical agents

Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression. It is therefore important to elucidate the mechanisms underlying UV-induced immunosuppression as a basis for developing strategies to protect individuals from this effect and subsequent development of skin cancer. Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis. In this review, we summarize the most recent investigations and mechanistic studies regarding the photoprotective efficacy of selected dietary agents, including, green tea polyphenols, grape seed proanthocyanidins and silymarin. We present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) the induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis.

Platelet-Activating Factor Is Crucial in Psoralen and Ultraviolet A-Induced Immune Suppression, Inflammation, and Apoptosis

Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA's mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects.

20 years after--milestones in molecular photobiology.

Ultraviolet radiation represents one of the most relevant environmental factors because of its hazardous health effects, which include induction of skin cancer, premature skin aging, and exacerbation of infectious diseases. The biologic effects exerted by ultraviolet radiation have been well characterized by a variety of in vitro and in vivo studies. The events taking place inside the cell during the ultraviolet response, however, remained unclear for quite a long time. Molecular photobiology has increased our knowledge about ultraviolet-induced signal transduction enormously within the last 10 years. For a long time, nuclear DNA has been regarded as the only chromophore for ultraviolet radiation. Today we know that ultraviolet radiation can affect also other molecular targets located in the cytoplasm and at the cell membrane. These targets include cell surface receptors, kinases, phosphatases, and transcription factors. Detailed knowledge about ultraviolet-induced signal transduction will certainly increase our understanding of how ultraviolet radiation exerts its biologic effects and furthermore will provide us with tools to interfere with these pathways, thereby reducing the adverse effects of ultraviolet radiation.

The effect of a vitamin A acetate diet on ultraviolet radiation-induced immune suppression as measured by contact hypersensitivity in mice.

The adverse health effects caused by increased exposure to ultraviolet radiation (UVR) due to deterioration of stratospheric ozone are of major concern. These health effects include sunburn, skin cancer, cataracts and immune suppression. Immune suppression has been associated with the release of cytokines, a defect in antigen presentation, induction of suppressor T cells and suppression of contact hypersensitivity (CH). CH is typically assessed by the mouse ear swelling test (MEST). Previous studies have demonstrated enhanced CH responses with vitamin A acetate (VAA) dietary supplementation assessed by MEST and the local lymph node assay (LLNA). To determine the effect that VAA has on UVR-induced immune suppression, we examined both the induction and elicitation phases of CH using murine models. The MEST was used to evaluate the interaction of UVR and VAA on CH elicitation. However, a positive MEST response requires that the induction phase as well as the elicitation phase of CH be functional. The LLNA was used to evaluate the interaction of UVR and VAA only on CH induction. We tested the hypothesis that mice maintained on a VAA-enriched diet are more resistant to UVR-induced immune suppression (CH) than those maintained on a control diet. Mice were maintained on a VAA-enriched or the control diet for 3 weeks and then exposed to UVR 3 days prior to sensitization with 2,4-dinitrofluorobenzene (DNFB). VAA enhanced the MEST response in both UVR-exposed and non-UVR-exposed mice. The VAA-enriched diet did not significantly alter the LLNA response in either UVR- or non-UVR-exposed mice. However, there was significant suppression in CH by UVR as measured by the LLNA. These results indicate that (1) the VAA-enriched diet does not restore the number of proliferating cells in the CH induction phase of UVR-induced immunosuppression; (2) the immunosuppressive effects of UVR affect the induction phase of CH; and (3) the LLNA should be examined as an alternative to the MEST for measurement of UVR-induced immunosuppression. The data indicate that the VAA-enriched diet enhanced the elicitation response (MEST) but not the earlier induction phase (LLNA). Further studies are necessary to define mechanisms of action, but modulation of cytokines and effects of specific lymphocyte subsets, as well as systemic effects and local modulation at the site of elicitation are possible. Additionally, future studies to evaluate the effect of the VAA-enriched diet when multiple doses of both UVR and DNFB are used would be of interest for both the LLNA and MEST end-points.

Dose-dependent induction of IL-12 but not IL-10 from human keratinocytes after exposure to ultraviolet light A.

Ultraviolet light A (UVA) is shown to play an augmentative or synergistic role with UVB in pathophysiological conditions induced by solar radiation. Thus, UVA would contribute significantly to the development of skin malignancies. It remains unclear, however, how UVA contributes to solar radiation-induced immune suppression. Keratinocytes (KC) produce cytokines which are a significant mediator of inflammatory and immunologic reactions in skin exposed to solar radiation and are a potent mediator in the induction of immune suppression. To examine if UVA alters the expression and production of cytokines from KC, normal human keratinocytes (HuSK) were cultured and exposed to UVA at doses ranging between 2.5 and 20 kJ/m2. Constitutive expression of the p35 subunit of interleukin (IL)-12 was detected by reverse transcription-polymerase chain reaction (RT-PCR) and the p40 subunit was induced by UVA irradiation dose dependently. IL-12 protein was also detected in the supernatants from UVA-irradiated HuSK by enzyme-linked imuunosorbent assay (ELISA) and confirmed by a bioassay. On the other hand, the same doses of UVA did not induce IL-10 mRNA or IL-10 protein which has been shown to be one of the cytokines responsible for the induction of UVB-induced immunosuppression. Considering that IL-12 promotes activation of Th1 cells and prevents the activation of Th2 cells and that administration of IL-12 has been shown to block the induction of immune suppression in UV-irradiated animals, our results suggest that UVA modulates skin immune function distinctively from UVB by affecting the balance between IL-10 and IL-12 produced from KC.

Commercial Sunscreen Lotions Prevent UV Radiation-Induced Immune Suppression of Contact Hypersensitivity

Commercial Sunscreen Lotions Prevent UV Radiation-Induced Immune Suppression of Contact Hypersensitivity

Commercial Sunscreen Lotions Prevent UV Radiation-Induced Immune Suppression of Contact Hypersensitivity

Department of Dermatology Medical College of Pennsylvania and Hahnemann University Philadelphia, PA

The role of epidermal cytokines in the generation of cutaneous immune reactions and ultraviolet radiation-induced immune suppression.

The role of epidermal cytokines in the generation of cutaneous immune reactions and ultraviolet radiation-induced immune suppression.

Effects of Sunscreens and a DNA Excision Repair Enzyme on Ultraviolet Radiation-Induced Inflammation, Immune Suppression, and Cyclobutane Pyrimidine Dimer Formation in Mice

Exposure of skin to ultraviolet (UV) radiation inhibits the induction of delayed-type hypersensitivity (DTH) responses initiated at a distant, unirradiated site. Recent studies attributed this form of immune suppression to DNA damage in the form of cyclobutane pyrimidine dimers (CPD). In the present study, we investigated the protective defects of sunscreens on UV-induced systemic suppression of DTH to Candida albicans, inflammation, and DNA damage. The photoprotective effects of sunscreen preparations containing 8% octyl-N-dimethyl-p-aminobenzoate, 7.5% 2-ethylhexyl-p-methoxycinnamate, or 6% benzophenone-3 were studied in C3H mice exposed to a single dose of 500 mJ/cm2 UVB radiation from FS40 sunlamps. Inflammation was determined by the amount of skin edema at the site of UV irradiation, and DNA damage was assessed by measuring the frequency of endonuclease-sensitive sites in the epidermis. Application of the sunscreens before UV irradiation gave 75-97% protection against UV-induced edema, 67-91% protection against formation of CPD, but only 30-54% protection against suppression of DTH. In contrast, the topical application of liposomes containing a CPD-specific DNA repair enzyme immediately after UV irradiation resulted in 82% protection against suppression of DTH, but at best, 39% protection against skin edema. These findings demonstrate that sunscreens give less protection against UV-induced immune suppression than against skin edema and CPD formation. Furthermore, they suggest that less DNA damage is required to cause UV-induced immune suppression than to cause sunburn.

The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance

An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that “Interferon” is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids.

Opiate antinociception is altered by immunemodification: the effect of inteferon, cyclosporine and radiation-induced immune suppression upon acute and long-term morphine activity

It has recently been demonstrated that various forms of immune modification result in a profound attenuation of the opiate withdrawal syndrome. Herein we investigate the extent to which some of the immune modifiers active in withdrawal attenuation affect other opiate related behaviors, namely antinociception and the development of tolerance to this effect. The observations demonstrate that immune modification by cyclosporine and irradiation exposure result in an alteration of the acute antinociceptive effect of morphine; while none of these treatments modify the development of tolerance to this property of morphine.

Studies on cyclophosphamide-induced tolerance to sheep erythrocytes.

Complete immunological tolerance to sheep cells can be induced in mice when cyclophosphamide is injected together with sheep cells or up to 72 hr before or 48 hr after the antigen. As is true for radiation-induced immune suppression, the drug is most effective when given in the 24 hr prior to antigen. Complete cyclophosphamide-induced immunological suppression requires large doses of sheep cells (6.2 x 10(9) cells), presumably to enable antigen to reach sequestered receptor sites. The cyclophosphamide tolerance system has been analyzed with the Jerne technique to determine plaque-forming cells and with isotopic methods to measure rates of nucleic acid synthesis. This drug suppression has been found to consist of two components. The first is nonspecific injury to the lymphoid system caused by the cytotoxic drug and is related to the proportion of spleen cells killed. The second is antigen-specific immunological tolerance and appears to correlate with profound depression of deoxyribonucleic acid synthesis in the surviving cells. This tolerance is thought to be most consistent with a mechanism in which antigenic stimulation in the presence of cyclophosphamide-inhibited DNA synthesis and mitosis leads to the elimination or death of the specific immunological clone. Tolerance induction with cyclophosphamide is associated with loss of the 19S hemolysin plaques which are seen in nonstimulated mouse spleen, implicating these cells in immune responsiveness. The ability to induce tolerance is lost on the 3rd postantigen day at the end of a 24-hr period in which 19S cells have increased 8-fold and 7S cells 200-fold. The data suggest that loss of sensitivity is due to the emergence on day 3 of drug-resistant plaque-forming cells, particularly those of the 19S variety. In the succeeding days after antigen injection there is a progressive increase in the resistance of plaque-forming cells to cyclophosphamide administration.