In human monocyte‐derived macrophages, the MCPIP gene (monocyte chemoattractant protein‐induced protein) is strongly activated by interleukin‐1β (IL‐1β). Using bioinformatics, a PIN domain was identified, spanning amino acids 130‐280; such domains are known to possess structural features of RNases. Recently, RNase properties of MCPIP were confirmed on transcripts coding for interleukins IL‐6 and IL‐12p40. Here we present evidence that siRNA‐mediated inhibition of the MCPIP gene expression increases the level of the IL‐1β transcript in cells stimulated with LPS, whereas overexpression of MCPIP exerts opposite effects. Cells with an increased level of wild‐type MCPIP showed lower levels of IL‐1β mRNA. However, this was not observed when mutant forms of MCPIP, either entirely lacking the PIN domain or with point mutations in this domain, were used. The results of experiments with actinomycin D indicate that lower levels of IL‐1β mRNA are due to shortening of the IL‐1β transcript half‐life, and are not related to the presence of AU‐rich elements in the 3′ UTR. The interaction of the MCPIP with transcripts of both IL‐1β and MCPIP observed in an RNA immunoprecipitation assay suggests that this novel RNase may be involved in the regulation of expression of several genes.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Globally, it is currently the most common liver disease and is estimated to affect up to 25% of the population. In the first stage, NAFLD is characterized by simple hepatic steatosis (NAFL, nonalcoholic fatty liver) that might progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular carcinoma. In this review, we discuss the global burden of NAFLD, together with future perspectives on how this epidemic could be restrained. There is also an urgent need for the development of new medical strategies for NAFLD patients. We aim to present the beneficial effects of life-style modifications that should be advised to both non-obese and obese NAFLD patients. Since there are currently no medications directly used for the treatment of more advanced NAFLD stages, the central part of this review summarizes ongoing and recently completed clinical trials testing promising drugs for NASH resolution. The marketing of new therapeutic agents would greatly increase the odds of reducing the global burden of NAFLD.

Ribonucleic acids (RNAs) are very complex and their all functions have yet to be fully clarified. Noncoding genes (noncoding RNA, sequences, and pseudogenes) comprise 67% of all genes and they are represented by housekeeping noncoding RNAs (transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), and small nucleolar RNA (snoRNA)) that are engaged in basic cellular processes and by regulatory noncoding RNA (short and long noncoding RNA (ncRNA)) that are important for gene expression/transcript stability. In this review, we summarize data concerning the significance of long noncoding RNAs (lncRNAs) in metabolic syndrome related disorders, focusing on adipose tissue and pancreatic islands.

A novel gene ZC3H12A, encoding MCP‐1‐induced protein 1 (MCPIP), was recently identified in human peripheral blood monocytes treated with monocyte chemotactic protein 1 (MCP‐1) and in human monocyte‐derived macrophages stimulated with interleukin (IL)‐1β. These experiments revealed that the gene undergoes rapid and potent transcription induction upon stimulation with proinflammatory molecules, such as MCP‐1, IL‐1β, tumour necrosis factor α and lipopolysaccharide. Here we show that the induction of ZC3H12A by IL‐1β is predominantly NF‐κB‐dependent because inhibition of this signalling pathway results in the impairment of ZC3H12A transcription activation. Our results indicate the presence of an IL‐1β‐responding region within the second intron of the ZC3H12A gene, which contains four functional NF‐κB‐binding sites. Therefore, we propose that this transcription enhancer transduces a ZC3H12A transcription‐inducing signal after IL‐1β stimulation. Recent reports suggest that MCPIP acts as a negative regulator of inflammatory processes because it is engaged in the degradation of transcripts coding for certain proinflammatory cytokines. Our observations provide evidence for a novel negative feedback loop in the activation of NF‐κB and point to potential significance of MCPIP in the treatment of various pathological states, such as diabetes or cancer that involve disturbances in the functioning of the NF‐κB system.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL6, IL1, and IL12. MCPIP1 is also a negative regulator of NFκB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patient-derived tumors and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumor outgrowth, and vascularity. MCPIP1 activity regulated secretion of VEGF, IL8, and CXCL12 leading to chemotaxis of microvascular endothelial cells, phosphorylation of VE-cadherin, and increased vascular permeability. Mechanistic investigations showed that MCPIP1 regulated ccRCC cell motility, lung metastasis, and mesenchymal phenotype by regulating key elements in the EMT signaling axis. Overall, our results illuminate how MCPIP1 serves as a key nodal point in coordinating tumor growth, angiogenesis, and metastatic spread in ccRCC. Cancer Res; 77(18); 4905–20. ©2017 AACR.