Aryl Hydrocarbon Receptor-Dependent and -Independent Pathways Mediate Curcumin Anti-Aging Effects.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose activity can be modulated by polyphenols, such as curcumin. AhR and curcumin have evolutionarily conserved effects on aging. Here, we investigated whether and how the AhR mediates the anti-aging effects of curcumin across species. Using a combination of in vivo, in vitro, and in silico analyses, we demonstrated that curcumin has AhR-dependent or -independent effects in a context-specific manner. We found that in Caenorhabditis elegans, AhR mediates curcumin-induced lifespan extension, most likely through a ligand-independent inhibitory mechanism related to its antioxidant activity. Curcumin also showed AhR-independent anti-aging activities, such as protection against aggregation-prone proteins and oxidative stress in C. elegans and promotion of the migratory capacity of human primary endothelial cells. These AhR-independent effects are largely mediated by the Nrf2/SKN-1 pathway.

AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells.

Background Aryl hydrocarbon receptor (AHR)-deficient mice do not support the expansion of dendritic epidermal T cells (DETC), a resident immune cell population in the murine epidermis, which immigrates from the fetal thymus to the skin around birth. Material and Methods In order to identify the gene expression changes underlying the DETC disappearance in AHR-deficient mice, we analyzed microarray RNA-profiles of DETC, sorted from the skin of two-week-old AHR-deficient mice and their heterozygous littermates. In vitro studies were done for verification, and IL-10, AHR repressor (AHRR), and c-Kit deficient mice analyzed for DETC frequency. Results We identified 434 annotated differentially expressed genes. Gene set enrichment analysis demonstrated that the expression of genes related to proliferation, ion homeostasis and morphology differed between the two mouse genotypes. Importantly, with 1767 pathways the cluster-group "inflammation" contained the majority of AHR-dependently regulated pathways. The most abundant cluster of differentially expressed genes was "inflammation." DETC of AHR-deficient mice were inflammatory active and had altered calcium and F-actin levels. Extending the study to the AHRR, an enigmatic modulator of AHR-activity, we found approximately 50% less DETC in AHRR-deficient mice than in wild-type-littermates. Conclusion AHR-signaling in DETC dampens their inflammatory default potential and supports their homeostasis in the skin.

Effects of a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin, given at post-puberty, in senescent mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin is a well-known immunosuppressive environmental pollutant. TCDD interferes with physiological signaling of the arylhydrocarbon receptor, leading to cell-specific changes in gene transcription and cell differentiation. With respect to the immune system, the T-cell lineage and B-cell lineages are particularly affected. Although a single dose given to mice is excreted within weeks, these changes in differentiation may have long-term consequences for immune competence. We studied the effects of a single dose of TCDD given to young mice on some parameters of their immune system after they had aged almost to the end of their lifespan. Groups of 15 mice were given either 2.5 microg TCDD/kg b.w. or 25 microg TCDD/kg b.w. at the age of 8-12 weeks, and were analyzed between 16 and 21 months of age. Survival was equal in all groups. Blood glucose levels did not differ, and glucose tolerance after oral challenge was normal in old control mice and TCDD-exposed mice. No differences in the frequencies of B-cells, T-cells, or NK-cells were detectable. TCDD-exposed mice at both doses had a significantly higher titer of IgM compared to controls. Histological examination of pancreas, liver, kidney, spleen, and lungs yielded no differences, except for the lungs, where a significantly higher number of animals displayed activated BALT. In conclusion, our data suggest that a single dose of TCDD in young mice is correlated to activated secondary lymphoid tissues and high IgM titers. Both findings are congruent with a weakened immune system.

Allelic variants of drug metabolizing enzymes as risk factors in psoriasis.

The onset or exacerbation of psoriasis, a T-cell-dependent skin disease with autoimmune features, can be triggered by drugs such as antimalarials and beta-blockers. Xenobiotics may also play a role in idiopathic psoriasis. It has been hypothesized that different metabolic efficiencies caused by variant alleles of xenobiotic metabolizing enzymes could lead to the accumulation of xenobiotics or their reactive metabolites in target organs. Subsequently, neoantigens or cryptic peptides could be presented and initiate an aggressive T cell response. In this context, we analyzed a broad array of xenobiotic metabolizing enzymes in up to 327 Caucasian psoriasis patients and compared them to 235 control persons. Alleles tested include four phase I and three phase II enzymes. Significantly more carriers of the variant alleles of CYP1A1 (alleles *2A and *2C) were found in healthy controls than in patients, suggesting a protective role for these alleles. No significant difference between patients and controls could be found, however, for the other phase I alleles 1B1*1 and 1B1 *3, 2C19*1A and 2C19*2A, and 2E1*1A and 2E1*5B. Of the variant alleles coding for phase II enzymes only GSTM1, but not GSTT1 or NQOR, correlated with a risk to contract psoriasis. Some combinations of phase I and phase II enzymes suggested protective or risk-associated effects. Interestingly, heterozygosity for CYP2C19 alleles *1A and *2A was associated with increased risk for "late onset" psoriasis, whereas this genotype was protective for psoriatic arthritis. This is the first large-scale study on these enzymes and the results obtained support the concept that different activities of metabolizing enzymes can contribute to disease etiology and progression.