IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations.

In animal models, IL-12 and IL-23 participate in the development of malignant neoplasms of keratinocytes. However, the role of these cytokines in pigmented lesion development and their progression to melanoma has received little attention. IL-12p35, IL-23p19, and IL-12/IL-23p40 knockout mice on a C3H/HeN background, subjected to a melanomagenesis protocol, demonstrated profound differences in susceptibility to nevus initiation, transformation, tumorigenicity, and metastatic potential. IL-23 was found to be essential for melanocyte homeostasis, whereas IL-12 supported nevus development. A direct action of IL-23 on primary melanocytes, shown to be IL-23R+, demonstrated that DNA repair of damaged melanocytes requires IL-23. Furthermore, IL-23 modulated the cutaneous microenvironment by limiting regulatory T cells and IFN-γ and inhibiting IL-10 production. Neutralizing Ab to IFN-γ, but not IL-17, inhibited nevus development (p < 0.01).

TET1 controls CNS 5-methylcytosine hydroxylation, active DNA demethylation, gene transcription, and memory formation.

Dynamic changes in 5-methylcytosine (5mC) have been implicated in the regulation of gene expression critical for consolidation of memory. However, little is known about how these changes in 5mC are regulated in the adult brain. The enzyme methylcytosine dioxygenase TET1 (TET1) has been shown to promote active DNA demethylation in the nervous system. Therefore, we took a viral-mediated approach to overexpress the protein in the hippocampus and examine its potential involvement in memory formation. We found that Tet1 is a neuronal activity-regulated gene and that its overexpression leads to global changes in modified cytosine levels. Furthermore, expression of TET1 or a catalytically inactive mutant (TET1m) resulted in the upregulation of several neuronal memory-associated genes and impaired contextual fear memory. In summary, we show that neuronal Tet1 regulates DNA methylation levels and that its expression, independent of its catalytic activity, regulates the expression of CNS activity-dependent genes and memory formation.