RESUMEN
In mouse skin models, mast cells have been shown to express vitamin D receptor (VDR) that can mediate the immunosuppressive effects of ultraviolet B radiation and vitamin D3. However, VDR activation leads to the expression of CYP24A1, a hydroxylase that can inactivate vitamin D3 metabolites. To examine immunoreactivity to VDR and CYP24A1 in mast cells from normal human skin, keratinocyte skin cancers, and disorders of chronic inflammation. Frozen biopsies were collected from the non-lesional and lesional skin of patients with actinic keratosis (AK), Bowen's disease/squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and psoriasis. The expression of VDR and CYP24A1 in tryptase-positive mast cells was analysed using double-staining methods. Less than 0.5% of the mast cells were immunoreactive to VDR in both the non-lesional and lesional skin for all disease groups. In non-lesional skin, only 0.5-2.9% of the mast cells were immunopositive for CYP24A1, however, the percentage of mast cells containing CYP24A1 was significantly increased in lesional skin of AK, SCC, and BCC. In contrast to human skin, LAD2 mast cells cultured from a patient with mast cell sarcoma/leukaemia revealed that about 34% and 6.5% of the cells were immunopositive for VDR and CYP24A1, respectively. Whereas a very small proportion of mast cells in human skin express VDR and CYP24A1, the proportion of mast cells expressing CYP24A1 in keratinocyte skin cancers is increased; the mechanism underlying this is unclear.
Asunto(s)
Queratinocitos/inmunología , Mastocitos/inmunología , Receptores de Calcitriol/inmunología , Neoplasias Cutáneas/inmunología , Vitamina D3 24-Hidroxilasa/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Enfermedad de Bowen/inmunología , Enfermedad de Bowen/patología , Calcifediol/inmunología , Carcinoma Basocelular/inmunología , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Dihidroxicolecalciferoles/inmunología , Femenino , Humanos , Masculino , Mastocitos/efectos de los fármacos , Persona de Mediana Edad , Psoriasis/inmunología , Psoriasis/patología , Receptores de Calcitriol/análisis , Piel/química , Piel/citología , Piel/inmunología , Neoplasias Cutáneas/patología , Triptasas/análisis , Vitamina D3 24-Hidroxilasa/análisisRESUMEN
Male fetus and neonates show increased immune vulnerability compared to females, which results in a higher risk of perinatal infections. These differences could partially be due to sex steroids differential modulation of vitamin D metabolism; since calcitriol, the most active vitamin D metabolite, regulates immune responses and transcriptionally induces the antimicrobial peptide cathelicidin in the human placenta. Calcitriol availability depends on CYP27B1 and CYP24A1 expression, the cytochromes involved in its synthesis and degradation, respectively. However, the effects of testosterone upon these enzymes and the final biological outcome upon the calcitriol-dependent immune-target cathelicidin in the placenta have not been studied. In this study we show that testosterone significantly inhibited CYP27B1 while stimulated CYP24A1 gene expression in cultured trophoblasts. These effects were accompanied by CREB activation through cAMP-independent and androgen receptor-dependent mechanisms. Male placental cotyledons showed reduced basal CYP27B1 and cathelicidin gene expression compared to females (P<0.05). Testosterone concentration was higher in the cord blood of male neonates (P=0.007), whereas cathelicidin levels were lesser compared to females (P=0.002). Altogether our results suggest that male placentas produce less cathelicidin due to decreased calcitriol bioavailability. We propose that the observed sex-dependent differences in placental vitamin D metabolism contribute in fetal responses to infections and could partially explain why the increased male fetuses immune vulnerability. Moreover, gestational hyperandrogenemia could adversely affect placental vitamin D metabolism independently of fetal sex.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Catelicidinas/genética , Testosterona/farmacología , Trofoblastos/efectos de los fármacos , Vitamina D3 24-Hidroxilasa/genética , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/inmunología , Péptidos Catiónicos Antimicrobianos , Catelicidinas/inmunología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/inmunología , Femenino , Feto , Regulación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunidad Innata , Masculino , Embarazo , Cultivo Primario de Células , Receptores Androgénicos/genética , Receptores Androgénicos/inmunología , Caracteres Sexuales , Transducción de Señal , Testosterona/metabolismo , Trofoblastos/citología , Trofoblastos/inmunología , Vitamina D/farmacología , Vitamina D3 24-Hidroxilasa/inmunologíaRESUMEN
While many global mechanisms of innate immune responses to pathogen threat are conserved over a vast range of species, the details of those responses and their regulation appear to be highly species-specific. An array of studies over recent years has revealed that hormonal vitamin D is an important regulator of innate immunity. In humans, the hormone-bound VDR directly induces the transcription of genes encoding antimicrobial peptides (AMPs), pattern recognition receptors and key cytokines implicated in innate immune responses. We find that the vitamin D response elements (VDREs) in a number of these human genes are highly conserved in a range of primates, but not present in rodent genes. Consistent with this, VDR target genes encoding AMPs human beta-defensin 2 (HBD2) and cathelicidin (CAMP) and the pattern recognition receptor NOD2 are induced by 1,25(OH)2D in human cells of epithelial or myeloid origin but not similarly regulated in mouse cells. In addition, while conditioned media from human epithelial cells treated with 1,25(OH)2D produced antimicrobial activity against E. coli and the lung pathogen Pseudomonas aeruginosa, no such activity was detected in conditioned media from comparable 1,25(OH)2D-treated mouse epithelial cells. Given that other work has provided evidence that 1,25(OH)2D does control innate immune responses in mouse models of disease, we discuss the species-specific similarities and differences in 1,25(OH)2D-regulated innate immunity.