Lipoteichoic acid from Lactobacillus rhamnosus GG as an oral photoprotective agent against UV-induced carcinogenesis.

Probiotics are live micro-organisms that when administered in adequate amounts confer a health benefit on the host. Cell surface molecules of these micro-organisms are being studied in relation to their ability to interact with the host. The cell wall of lactobacilli possesses lipoteichoic acids (LTA) which are molecules with immunomodulatory properties. UV radiation (UVR) has been proposed as the main cause of skin cancer because of its mutagenic and immunosuppressive effects. Photoprotection with some nutrition interventions including probiotics has recently been shown. The aim of the present study was to investigate whether the oral administration of purified LTA from Lactobacillus rhamnosus GG can modulate the immune-suppressive effect of UVR and skin tumour development in female Crl:SKH-1-hrBR mice. For this purpose, two irradiation models were studied: (1) a chronic irradiation scheme consisting of daily irradiations during twenty consecutive days and (2) a long-term irradiation schedule, irradiating the animals three times per week, during 34 weeks for tumour development. The results showed that T-cells in the inguinal lymph node of LTA-treated mice produced higher levels of (1) interferon-γ and (2) a number of total, helper and cytotoxic T-cells compared with non-treated mice. Moreover, a significant delay in tumour appearance was found in LTA-treated mice. An increased IgA⁺ cell number was found in the small intestine together with a higher number of activated dendritic cells in the mesenteric lymph nodes. The latter results might be indicative of a direct effect of LTA in the gut, affecting the cutaneous immune system and restoring homeostasis through the gut-skin axis.

Skin exposure to chronic but not acute UV radiation affects peripheral T-cell function.

Ultraviolet (UV) radiation (UVR) produces deleterious effects that may finally lead to carcinogenesis. These adverse effects include tissue inflammation, free radical formation with consequent oxidation of proteins and lipids, DNA damage, and immune function suppression. The aim of this study was to evaluate the effects of UVR at the local and systemic levels following acute (4 consecutive days with 0.5 minimal erythema dose [MED]) or chronic (20 consecutive days with 0.25 MED) exposure. Locally, histological alterations and epidermal T-cell populations were studied. Systemically, inguinal lymph-node and spleen T cells were analyzed with respect to proliferative response and cytokine production against a nonspecific mitogen. Lymph-node T-cell populations were also characterized. Our results indicated that while both acute and chronic UVR produced epidermal hyperplasia and a decrease in epidermal T-cell density, acute UVR increased T-cell proliferative response, while chronic UVR produced the opposite effect, shifting the cytokine production toward a Th2/Treg profile. Therefore, even though acute irradiation produced a direct effect on skin, it did not correlate with a marked modification of overall T-cell response, which is in contrast to marked effects in chronically irradiated animals. These findings may contribute to understanding the clinical relevance of occupational UVR exposure, typically related to outdoor activities, which is associated with nonmelanoma skin carcinogenesis.

Anti-ribonucleoproteins autoantibodies in patients with systemic autoimmune diseases. Relation with cutaneous photosensitivity.

A common feature between patients with a certain group of systemic autoimmune pathologies (SAPs) with rheumatic component, such as lupus erythematosus (LE) in all its forms, is the presence of cutaneous photosensitivity (CP) as well as the existence of autoantibodies (Aabs). These Aabs have also high incidence in other SAPs that do not present CP, like primary Sjögren's syndrome and rheumatoid arthritis. Cutaneous photosensitivity is a condition that consists of an exacerbated skin reaction to solar radiations; its incidence can reach 90% in systemic LE. The mechanisms involved in the development of CP have been extensively studied focusing on different approaches; however, the exact mechanism has not been fully elucidated yet. There are many theories that relate specifically the presence of circulating anti-Ro/SS-A Aabs with the CP phenomenon, though there are several studies which are in disagreement. In this study, we evaluated the Aabs profile (anti-Ro/SS-A 52 kDa, anti-Ro/SS-A 60 kDa, anti-La/SS-B, anti-Sm and ANAs) as well as their titer or reactivity, in a local cohort of 169 patients with SAPs. We related those Aabs profiles and titers with the presence or absence of CP, and we found that there was no significant association between the presence of anti-Ro/SS-A Aabs and the occurrence of CP. On the other hand, a statistically significant positive association was found between CP and high reactivity anti-Sm Aabs, though this fact could be biased by the incidence of both events in SLE patients. To sum up, in the particular population studied, there is no direct relationship between anti-Ro/SS-A Aabs and CP, which is in agreement with some authors and in disagreement with many others, contributing to the endless discussion of this issue.

Alterations in skin immune response throughout chronic UVB irradiation-skin cancer development and prevention by naproxen.

Skin exposure to UVB radiation has been reported to produce both a significant inflammatory response and marked immunosuppression. This work was aimed to evaluate whether the response of murine skin to an acute UVB dose was modified by pre-exposure to chronic UVB irradiation and by topical treatment with naproxen, a nonsteroidal anti-inflammatory drug. Moreover, the effect of naproxen on the incidence of UV-induced skin tumors was studied. Prostaglandin E(2) (PGE(2)) and tumor necrosis factor alpha (TNF-alpha) levels were increased 96 h post-UVB in acutely irradiated animals and both mediators were modified by topical naproxen application-PGE(2) was decreased while TNF-alpha was increased. Such inflammatory response was suppressed when mice were chronically irradiated. Naproxen application on chronically irradiated mice reduced the incidence of tumor lesions. Taken together, our data suggest that chronic UVB irradiation generates an immunosuppressive state that prevents skin cells from responding normally to an acute irradiation challenge, thus impairing the protective effect of TNF-alpha against skin tumor development. Furthermore, reduction in the incidence of tumor lesions by naproxen may be due to its ability to increase TNF-alpha levels as well as to decrease PGE(2).

Time-course evaluation and treatment of skin inflammatory immune response after ultraviolet B irradiation.

Skin exposure to high doses of ultraviolet B (UVB) radiation generates a severe inflammatory skin response. In the present study we aim to investigate, using in vitro and in vivo models, the time-course of the inflammatory skin immune response after an acute exposure to UVB irradiation, as well as its modulation by a topical non-steroidal anti-inflammatory drug (NSAID) treatment, naproxen. PGE2 production and TNF-alpha levels increase in a post-irradiation time-dependent manner both in vivo and in vitro. This production pattern is also reflected in the iNOS expression levels in vivo and in the IL-6 levels in vitro. Changes observed in these mediators are correlated with histological alterations and dermal infiltration after the acute UVB irradiation. Naproxen treatment notably reduces PGE2 production and iNOS expression, reflecting the COX-NOS crosstalk already reported, although it causes an important increment in TNF-alpha synthesis in the epidermis of irradiated mice. Taken together, our data indicates that the epidermis is severely damaged by UVB radiation but then it is able to fully recover, and that the immune response is modulated by the NSAID treatment, since it is able to reduce the levels of some mediators as well as it can increase others.

Mitochondrial dysfunction and cellular stress progression after ultraviolet B irradiation in human keratinocytes.

BACKGROUND: Ultraviolet (UV) radiation is the major environmental harmful factor that affects human skin. UVB radiation is known to be a potent inducer of reactive oxygen species (ROS) production and has also been associated with the generation of nitric oxide (NO), all of which have been implicated in various skin disorders. It is well known that mitochondria can also be affected by UVB, leading to alterations in their membrane structure and permeabilization with cytochrome c release, which consequently affects the cell function. However, the loss of keratinocyte mitochondrial function generated by UVB, as well as its kinetics, has not been characterized completely. METHODS: We evaluated the effect of UVB irradiation on HaCat cells' mitochondrial function, assessed by membrane potential loss and superoxide anion (O(2)(*-)) production, correlating with apoptosis, p53 expression, ROS levels and NO production, 0, 6, 12, 24 and 48 h post-irradiation. RESULTS: HaCat cells progressed toward apoptotic cell death as the time post-irradiation increased, with the highest levels found 48 h after irradiation. Increased levels of ROS were observed 6 h after irradiation while high O(2)(*-) levels and mitochondrial membrane depolarization were detected 12 h post-UVB. Nevertheless, NO production was not significantly increased at any of the evaluated times. CONCLUSIONS: The kinetics of mitochondrial dysfunction after UVB irradiation in human keratinocytes progressed in a time post-irradiation-dependent manner, and they are closely related to cell death. However, there are certain levels of apoptosis, although low, in the absence of mitochondrial alterations. In addition, our data suggest that ROS play a greater role in keratinocyte UVB damage than reactive nitrogen species.

Skin damage and mitochondrial dysfunction after acute ultraviolet B irradiation: relationship with nitric oxide production.

BACKGROUND: Ultraviolet (UV) radiation is the main environmental carcinogen. It is able to induce injury in the keratinocytes, which triggers mechanisms in order to protect the skin against molecular alterations that may lead to the development of skin cancer. UVB is capable of producing genotoxic damage, directly or indirectly through reactive oxygen species, inducing DNA alterations and mutations. UVB radiation has also been associated with the generation of nitric oxide (NO), which is able to induce many physiological and physiopathological processes. The aim of the current study was to investigate the effect of UVB irradiation in hairless mice skin. METHODS: We evaluated the effect of an acute dose (200 mJ/cm(2)) of UVB irradiation correlating with histological alterations, nitric oxide synthase expression and activity, mitochondrial respiratory function, superoxide anion production and lipid peroxidation, 0, 6, 17 and 24 h post-irradiation treatment. RESULTS: Morphological analysis showed disruption of the epidermal stratum corneum and basale after UVB irradiation. The results indicated that skin UVB irradiation was associated with an increased cytosolic inducible nitric oxide synthase (iNOS) expression, inversely related to lipid peroxidation processes. An increase in mitochondrial superoxide anion (O(2) (*-)) and NO production 17 h post-irradiation was correlated with a mitochondrial dysfunction, all of them integrating the skin response to acute UVB irradiation. CONCLUSIONS: UVB irradiation of the skin produces morphological alterations as a consequence of the induction of molecular mechanisms associated with mitochondrial respiratory dysfunction and O(2) (*-) production, probably mediated by the increased mitochondrial NO production. On the other hand lipid peroxidation decrease inversely correlates with cytosolic iNOS expression, suggesting a protective role for the inflammatory response.

[Isotype switch in the response against T independent antigens by co-inoculation with T dependent antigens]. / Cambio del isotipo en la respuesta a antígenos T independientes por co-inoculación con antígenos T dependientes.

A classical paradigm in immunology establishes that for the isotype switch to take place in antibodies, it is a sine qua non condition that the antigen is presented by an antigen presenting cell to a helper T cell. In the present study an animal model of the immune response against two typical antigens was designed in BALB/c mice. Dextran was chosen as a T independent antigen (TIAg), and bovine seroalbumin (BSA) as a T dependant antigen (TDAg), and the response was studied, analyzing the isotypes of the specific antibodies produced. The results show that the response against dextran, in the presence of BSA, takes place with isotype switch, essentially from IgM to IgG1. These experiments suggest that BSA generates a switch inductor biochemical environment in its own processing pathway as well as in the dextran's. These results indicate that the exclusive association of TDAgs with isotype switch responses is inaccurate. Considering the proposed model, it seems unlikely the finding of a spontaneous in vivo case in which TIAgs enter the organism isolated; instead, it is much more probable that they would enter together with TDAgs, and in consequence the isotype switch would take place.

Cambio del isotipo en la respuesta a antígenos T independientes por co-inoculación con antígenos T dependientes. / [Isotype switch in the response against T independent antigens by co-inoculation with T dependent antigens]

A classical paradigm in immunology establishes that for the isotype switch to take place in antibodies, it is a sine qua non condition that the antigen is presented by an antigen presenting cell to a helper T cell. In the present study an animal model of the immune response against two typical antigens was designed in BALB/c mice. Dextran was chosen as a T independent antigen (TIAg), and bovine seroalbumin (BSA) as a T dependant antigen (TDAg), and the response was studied, analyzing the isotypes of the specific antibodies produced. The results show that the response against dextran, in the presence of BSA, takes place with isotype switch, essentially from IgM to IgG1. These experiments suggest that BSA generates a switch inductor biochemical environment in its own processing pathway as well as in the dextrans. These results indicate that the exclusive association of TDAgs with isotype switch responses is inaccurate. Considering the proposed model, it seems unlikely the finding of a spontaneous in vivo case in which TIAgs enter the organism isolated; instead, it is much more probable that they would enter together with TDAgs, and in consequence the isotype switch would take place.