The innate RNA sensor RIG-I is critical in the initiation of antiviral type I interferons (IFNs) production upon recognition of "non-self" viral RNAs. Here, we identify a host-derived, IFN-inducible long noncoding RNA, lnc-Lsm3b, that can compete with viral RNAs in the binding of RIG-I monomers and feedback inactivate the RIG-I innate function at late stage of innate response. Mechanistically, binding of lnc-Lsm3b restricts RIG-I protein's conformational shift and prevents downstream signaling, thereby terminating type I IFNs production. Multivalent structural motifs and long-stem structure are critical features of lnc-Lsm3b for RIG-I binding and inhibition. These data reveal a non-canonical self-recognition mode in the regulation of immune response and demonstrate an important role of an inducible "self" lncRNA acting as a potent molecular decoy actively saturating RIG-I binding sites to restrict the duration of "non-self" RNA-induced innate immune response and maintaining immune homeostasis, with potential utility in inflammatory disease management.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC‐induced immunosuppression often leads to ineffectiveness of immuno‐promoting therapies. Currently, suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here, we identified one new subset of human CD14+CTLA‐4+ regulatory dendritic cells (CD14+DCs) in HCC patients, representing ∼13% of peripheral blood mononuclear cells. CD14+DCs significantly suppress T‐cell response in vitro through interleukin (IL)‐10 and indoleamine‐2,3‐dioxygenase (IDO). Unexpectedly, CD14+DCs expressed high levels of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and programmed death‐1, and CTLA‐4 was found to be essential to IL‐10 and IDO production. So, we identified a novel human tumor‐induced regulatory DC subset, which suppresses antitumor immune response through CTLA‐4‐dependent IL‐10 and IDO production, thus indicating the important role of nonregulatory T‐cell‐derived CTLA‐4 in tumor‐immune escape or immunosuppression. Conclusions: These data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14+DCs, which may contribute to HCC progression. This adds new insight to the mechanism for HCC‐induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC. (Hepatology 2014;59:567–579)
This article is available online at http://www.jlr.org Nonalcoholic fatty liver disease (NAFLD), characterized by excessive accumulation of triglyceride (TG) in the hepatocytes, affects from 10% to ف 39% of people worldwide ( 1, 2 ). It is closely associated with obesity ( 3 ), insulin resistance ( 4 ), and type 2 diabetes ( 5 ). We previously reported that in NAFLD patients without type 2 diabetes, up to 31.4% of individuals meet the criteria of metabolic syndrome, and 43.2% meet the criteria of impaired glucose regulation, of which 14.4% are newly diagnosed with diabetes ( 6 ). In a hamster model, preventing intrahepatic lipid accumulation abrogates the development of hepatic insulin resistance; a dose-dependent relationship exists ( 7 ). Shulman et al. reported that moderate weight loss normalizes fasting hyperglycemia and improves hepatic insulin sensitivity in patients with poorly controlled type 2 diabetes by reducing hepatic triglyceride content ( 8 ). Several prospective studies ( 4-6, 9 ) have also shown that NAFLD can predict type 2 diabetes and metabolic syndrome. Thus, reducing hepatic fat accumulation can be an effective strategy to prevent type 2 diabetes. As the pathogenesis of NAFLD remains unclear, no drug is generally accepted, and the only effective treatment is lifestyle intervention, including low-calorie diet, weight loss, and exercise ( 10 ).
Various technologies are currently available to quantify DNA methylation. However, rapid and simple methods for determining the DNA methylation status of CpG sites in genes still remain elusive. In this report, we describe a novel method for the rapid quantification of CpG methylation on the basis of direct bisulfite-PCR sequencing method. According to the principles of bisulfite-PCR, converting unmethylated cytosines to thymine while leaving methylated cytosines unchanged, we regard the CpG site as a SNP and estimate the methylation status of cytosines in the given CG dinucleotides by measuring the ratio of the cytosine peak height to the sum of cytosine and thymine peak heights in automated DNA sequencing traces. Furthermore, we take several effective measures to break through the 'bottleneck' problems that render the routine bisulfite sequencing method unsuitable for quantitative methylation. In comparison with pyrosequencing and bisulfite-cloning sequencing, our method is confirmed to be a simple, high-throughput and cost-effective technology for determining the methylation status of specific genes. Accordingly, this novel method is anticipated to be an efficient and economical alternative tool for rapid quantification of methylation patterns in screening large numbers of clinical samples across multiple genes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.