RESUMO
There is a continuing interest in whether Bisphenol A (BPA) is able to cause adverse health effects through interaction with elements of the immune system. That interest has been fuelled further by the recent publication of a draft opinion on BPA prepared by the European Food Safety Authority (EFSA) Panel on Food Contact Materials, Enzymes and Processing Aids (CEP). This draft opinion judged effects on the immune system to be the most sensitive health outcome, and identified BPA-induced changes in the frequency of T-helper (TH)-17 cells in the spleens of mice as being the critical effect based on an association of these cells with inflammation. Based on these evaluations the CEP Panel recommended that a revised Tolerable Daily Intake (TDI) for BPA of 0.04 ng/kg bw/day should be adopted; representing a very substantial reduction (100,000-fold) compared with the existing TDI. The purpose of this commentary is to summarize briefly the role of TH17 cells in immune responses, and to review relevant literature regarding the influence of BPA on these cells, and on inflammatory responses in the lung and respiratory allergy. The conclusion drawn is that based on uncertainties about the effects of BPA on TH17 cells and lung inflammation in mice, the absence of consistent or persuasive evidence from human studies that exposure of BPA is associated with inflammation or allergy, and unresolved questions regarding the species selectivity of immune effects induced by BPA, it is inappropriate to adopt the revised TDI. Additional research is required to explore further the influence of BPA on the immune system and immune responses.
Assuntos
Compostos Benzidrílicos , Hipersensibilidade , Animais , Compostos Benzidrílicos/toxicidade , Humanos , Inflamação , Camundongos , Fenóis , Medição de RiscoRESUMO
The transcription factor HIF-1a regulates cellular metabolism under hypoxia but also immune responses and UVB-induced skin reactions. In keratinocytes (KCs), HIF-1a is an environmental sensor orchestrating the adaptation to environmental changes. In this study, we investigated the role of HIF-1a in KCs for skin reactions to acute and chronic UVB exposure in mice. The function of HIF-1a in KCs under UVB exposure was analyzed in KC-specific HIF-1a conditional knockout (cKO) mice. cKO mice were hypersensitive to acute high-dose UVB irradiation compared with wild-type mice, displaying increased cell death and delayed barrier repair. After chronic low-dose UVB treatment, cKO mice also had stronger epidermal damage but reduced infiltration of dermal macrophages and T helper cells compared with wild-type mice. Irradiated cKO mice revealed accumulation of regulatory lymphocytes in dorsal skin-draining lymph nodes compared with wild-type and unirradiated mice. This was reflected by an augmented IL-10 release of lymph node cells and a weaker contact hypersensitivity reaction to DNFB in UVB-exposed cKO mice than in wild-type and unirradiated controls. In summary, we found that KC-specific HIF-1a expression is crucial for adaptation to UVB exposure and inhibits the development of UVB-induced immunosuppression in mice. Therefore, HIF-1a signaling in KCs could ameliorate photoaging-related skin disorders.
Assuntos
Queratinócitos , Raios Ultravioleta , Animais , Tolerância Imunológica , Terapia de Imunossupressão , Queratinócitos/metabolismo , Camundongos , Pele , Raios Ultravioleta/efeitos adversosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Cockayne syndrome (CS), a hereditary form of premature aging predominantly caused by mutations in the csb gene, affects multiple organs including skin where it manifests with hypersensitivity toward ultraviolet (UV) radiation and loss of subcutaneous fat. There is no curative treatment for CS, and its pathogenesis is only partially understood. Originally considered for its role in DNA repair, Cockayne syndrome group B (CSB) protein most likely serves additional functions. Using CSB-deficient human fibroblasts, Caenorhabditiselegans, and mice, we show that CSB promotes acetylation of α-tubulin and thereby regulates autophagy. At the organ level, chronic exposure of csbm/m mice to UVA radiation caused a severe skin phenotype with loss of subcutaneous fat, inflammation, and fibrosis. These changes in skin tissue were associated with an accumulation of autophagic/lysosomal proteins and reduced amounts of acetylated α-tubulin. At the cellular level, we found that CSB directly interacts with the histone deacetylase 6 (HDAC6) and the α-tubulin acetyltransferase MEC-17. Upon UVA irradiation, CSB is recruited to the centrosome where it colocalizes with dynein and HDAC6. Administration of the pan-HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) enhanced α-tubulin acetylation, improved autophagic function in CSB-deficient models from all three species, and rescued the skin phenotype in csbm/m mice. HDAC inhibition may thus represent a therapeutic option for CS.
Assuntos
Autofagia/efeitos dos fármacos , Síndrome de Cockayne/patologia , Inibidores de Histona Desacetilases/farmacologia , Lisossomos/metabolismo , Gordura Subcutânea/patologia , Acetilação , Animais , Autofagia/efeitos da radiação , Proteínas Relacionadas à Autofagia/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Centrossomo/efeitos dos fármacos , Centrossomo/metabolismo , Centrossomo/efeitos da radiação , DNA Helicases/deficiência , DNA Helicases/metabolismo , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/efeitos da radiação , Lisossomos/efeitos dos fármacos , Lisossomos/efeitos da radiação , Camundongos , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose/deficiência , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Pele/patologia , Pele/efeitos da radiação , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/efeitos da radiação , Tubulina (Proteína)/metabolismo , Proteínas Ubiquitinadas/metabolismo , Raios Ultravioleta , Vorinostat/farmacologiaRESUMO
Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR-/- mice, and critical for the improvement of NER. Besides increasing NER activity, AHR inhibition was accompanied by an enhanced occurrence of DNA double-strand breaks triggering KC apoptosis at later time points after irradiation. The UVB-activated AHR thus acts as a negative regulator of both early defense systems against carcinogenesis, NER and apoptosis, implying that it exhibits tumorigenic functions in UVB-exposed skin. In fact, AHR-/- mice developed 50% less UVB-induced cutaneous squamous cell carcinomas in a chronic photocarcinogenesis study than their AHR+/+ littermates. Taken together, our data reveal that AHR influences DNA damage-dependent responses in UVB-irradiated KC and critically contributes to skin photocarcinogenesis in mice.
Assuntos
Apoptose/efeitos da radiação , Reparo do DNA/efeitos da radiação , Neoplasias Induzidas por Radiação/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Raios Ultravioleta , Animais , Carcinoma de Células Escamosas/patologia , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Camundongos , Camundongos Pelados , Camundongos Knockout , Neoplasias Induzidas por Radiação/metabolismo , Dímeros de Pirimidina/análise , Dímeros de Pirimidina/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Neoplasias Cutâneas/patologiaRESUMO
Due to changes in human lifestyle (expanded sunbathing, the use of solaria, etc.) and, most importantly, increasing lifetime and thus higher cumulative exposure to solar radiation, skin aging and skin cancer have become major health issues. As a consequence effective photoprotection is of outmost importance to humans. In this regard a lot has been learned in the past about the cellular and molecular basis underlying ultraviolet (UV) radiation-induced skin damage and, based on this knowledge, numerous skin protective approaches including organic and inorganic UV-filters, but also topically applicable antioxidants, DNA repair enzymes and compatible solutes as well as oral photoprotective strategies based on nutritional supplements have been developed. A new aspect is here that sun protection of human skin might even be possible after solar radiation-induced skin damage has occurred. A second, very important development was prompted by the discovery that also wavelengths beyond the UV spectrum can damage human skin. These include the blue light region of visible light (VIS) as well as the near infrared range (IRA) and corresponding sunprotection strategies have thus recently been or are still being developed. In this article we will provide a state of the art summary of these two novel developments and, at the end, we will also critically discuss strengths and weaknesses of the current attempts, which mainly focus on the prevention of skin damage by selected wavelengths but greatly ignore the possibility that wavelengths might interfere with each other. Such combined effects, however, need to be taken into account if photoprotection of human skin is intended to be global in nature.