Histone/protein deacetylases (HDACs) regulate chromatin remodeling and gene expression as well as the functions of more than 50 transcription factors and nonhistone proteins. We found that administration of an HDAC inhibitor (HDACi) in vivo increased Foxp3 gene expression, as well as the production and suppressive function of regulatory T cells (T(reg) cells). Although T(reg) cells express multiple HDACs, HDAC9 proved particularly important in regulating Foxp3-dependent suppression. Optimal T(reg) function required acetylation of several lysines in the forkhead domain of Foxp3, and Foxp3 acetylation enhanced binding of Foxp3 to the Il2 promoter and suppressed endogenous IL-2 production. HDACi therapy in vivo enhanced T(reg)-mediated suppression of homeostatic proliferation, decreased inflammatory bowel disease through T(reg)-dependent effects, and, in conjunction with a short course of low-dose rapamycin, induced permanent, T(reg)-dependent cardiac and islet allograft survival and donor-specific allograft tolerance. Our data show that use of HDACi allows the beneficial pharmacologic enhancement of both the numbers and suppressive function of Foxp3(+) T(reg) cells.

Interleukin 10 (IL-10) has a prominent function in regulating the balance between protective and pathological T cell responses. Consistent with that activity, many sources of this cytokine are found in vivo, including from myeloid cells and a variety of T cell subsets. However, although there are many pathways that regulate innate production of IL-10, the factors that govern its synthesis by the adaptive response are poorly understood. Here we report that IL-27 and IL-6 induced T helper type 1 and type 2 cells, as well as T helper cells that produce IL-17, to secrete IL-10. This effect was dependent on the transcription factors STAT1 and STAT3 for IL-27 and on STAT3 for IL-6. Our studies identify a previously unknown pathway that allows the immune system to temper inflammatory responses.

No abstract

Merck.

The liver is the most common site of metastatic disease1. While this metastatic tropism may reflect mechanical trapping of circulating tumor cells, liver metastasis is also dependent, at least in part, on formation of a “pro-metastatic” niche that supports tumor cell spread to the liver2,3. Mechanisms that direct formation of this niche, though, are poorly understood. Here, we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver, and in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. Early during pancreatic tumorigenesis, hepatocytes demonstrate activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling and increased production of serum amyloid A1 and A2 (SAA). Overexpression of SAA by hepatocytes also occurs in pancreatic and colorectal cancer patients with liver metastases, and many patients with locally advanced and metastatic disease display elevated levels of circulating SAA. STAT3 activation in hepatocytes and the subsequent production of SAA are dependent on interleukin 6 (IL-6) that is released into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6/STAT3/SAA signaling prevents establishment of a pro-metastatic niche and inhibits liver metastasis. Our data reveal an intercellular network underpinned by hepatocytes that forms the basis for a pro-metastatic niche in the liver and identify new therapeutic targets.