RESUMO
Infrared A (IRA) radiation (760-1440 nm) is a major component of solar radiation and, similar to UVR, causes photoaging of human skin by increasing the expression of matrix metalloproteinase-1 in human skin fibroblasts. In this study, we assessed the IRA-induced transcriptome in primary human skin fibroblasts. Microarray analysis revealed 599 IRA-regulated transcripts. The IRA-induced transcriptome differed from changes known to be induced by UV. IRA-responsive genes include the categories extracellular matrix, calcium homeostasis, stress signaling, and apoptosis. Selected results were confirmed by real-time PCR experiments analyzing 13 genes representing these four categories. By means of chemical inhibitors of known signaling pathways, we showed that ERK1/2, the p38-, JNK-, PI3K/AKT-, STAT3-, and IL-6 as well as the calcium-mediated signaling pathways, are functionally involved in the IRA gene response and that a major part of it is triggered by mitochondrial and, to a lesser extent, non-mitochondrial production of reactive oxygen species. Our results identify IRA as an environmental factor with relevance for skin homeostasis and photoaging.
Assuntos
Fibroblastos/efeitos da radiação , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos da radiação , Raios Infravermelhos , Pele/efeitos da radiação , Apoptose/fisiologia , Apoptose/efeitos da radiação , Células Cultivadas , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos da radiação , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Homeostase/fisiologia , Homeostase/efeitos da radiação , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Pele/citologia , Pele/metabolismo , Estresse Fisiológico/fisiologia , Estresse Fisiológico/efeitos da radiação , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Atopic dermatitis (AD) is a chronic skin disease affecting up to 15% of children in industrialized countries. AD belongs to the group of atopic disorders characterized by excessive immune reactions to ubiquitous antigens. Complex interactions between genetic and environmental factors have been suggested for atopic disorders. Dysregulation of the innate immune system appears crucial for the pathogenesis of AD. The NACHT-LRRs (NLRs) represent a group of innate immune receptors with special relevance for inflammatory processes. In order to investigate the role of variation in NLR genes for AD, we genotyped 23 single nucleotide polymorphisms (SNPs) in seven selected NLR genes (CARD4, CARD15, CARD12, NALP1, NALP3, NALP12, MHC2TA) in 392 AD patients and 297 controls by restriction enzyme digestion or TaqMan assays. Single-SNP analysis demonstrated significant associations of the CARD15_R702W variation and the NALP12_In9 T-allele with AD (P = 0.008 and P = 0.03, resp.; insignificant after Bonferroni correction). In the CARD4 gene, a rare haplotype was more frequent in AD patients than in controls. Interactions between all pairs of SNPs in the seven genes were analysed by logistic regression. Significant interactions comprised SNPs in the CARD4 gene (CARD4_In1 and CARD4_Ex6, P = 6.56 x 10(-7); CARD4_Prom und CARD4_Ex6, P = 2.45 x 10(-4)) and promoter polymorphisms in the CARD12 and NALP1 genes (P = 4.31 x 10(-4)). In conclusion, variation in individual genes from the NLR family as well as interactions within this group of innate immune receptor genes could play a role in AD pathogenesis. Investigations in other populations and functional studies are warranted to clarify contributions of NLR variation for this frequent skin disease.