Inflammation is part of the physiological innate immune response to invading pathogens and tissue injury. However, unresolved inflammation leads to human disease. The tribbles (TRIB) family of pseudokinase proteins has been shown to modulate key inflammatory signalling pathways, including the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) networks. This review summarizes our current knowledge on TRIBs in the context of inflammation, both at the level of molecular mechanisms and in disease development.

IntroductionTribbles-1 (trib-1) pseudokinase is a regulatory protein that has been shown to be a protective gene in a number of cell types and processes, relevant to the development of atherosclerosis. These include inhibition of vascular smooth muscle cell proliferation, polarisation of macrophages towards an alternatively activated phenotype and lowering the production and release of LDL in hepatic tissues. Therefore, understanding the molecular mechanisms, which regulate trib-1 expression are of significant interest. Our group have identified miRNA202 as a controller of trib-1 levels.RationaleTrib-1 mRNA is highly unstable with a half-life of less than 1 h; the 3’ UTR encodes for a number of putative binding sites for miRNAs, including miRNA202. This study aimed to experimentally validate the importance of miRNA202 in the control of trib-1 expression.Methods1. We have used a luciferase reporter to demonstrate the role of trib-1 3’UTR in mRNA stability and to characterise the impact of miR202 on trib-1 3’UTR in hepatic cells (HepG2). 2. qRT-PCR was used to quantify endogenous trib-1 and miRNA202 levels upon stimulation of IL-1 and in high glucose media. 3. Western blotting was used to elucidate the effect of miRNA202 on trib-1 protein levels.Results1. Overexpression of miR202 reduced luciferase – trib1-3’UTR reporter expression. 2. The endogenous trb-1 mRNA was also modulated by miR202. Furthermore, stimulation of IL-1 in HepG2 cells has shown trb-1 levels to reduce by >70% and miR202 levels to increase by 2 fold. 3. Trib-1 protein levels have shown a reduction upon overexpression of miRNA202. Conversely, miRNA202 inhibitor increased trib-1 protein levels.DiscussionmiR202 is a novel regulator of trib-1 expression and may represent a target by which trib-1 levels could be raised in vivo, thereby providing a mechanism to augment the anti-atherosclerotic effects of this protein.

Conclusion The data show that higher levels of IgM antibodies, including IgM anti-MDA, are associated with a decreased coronary necrotic core volume and lipid core burden, whereas total serum IgG and IgG anti-MDA LDL antibodies were not related to the measured plaque characteristics. The ability of IgM antibodies but not HDL-or LDL-cholesterol levels to indicate these important plaque characteristics is consistent with a proposed mechanistic role. Pulmonary arterial hypertension (PAH) is a chronic and lifethreatening disease with high morbidity and mortality in adult and paediatric patients. PAH is characterised by a progressive narrowing and occlusion of small pulmonary arteries leading to increased pulmonary resistance, right ventricular hypertrophy, and, finally, right ventricular failure. 156A large body of data has shown that proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) represent key events in the vascular remodelling of pulmonary arteries that occurs during PAH. Levels of cytoplasmic calcium are an important determinant of PASMC proliferation and migration, and failure in maintaining appropriate levels of intracellular calcium are associated with PAH. The plasma membrane calcium ATPase (PMCA) proteins extrude calcium from the cytosol to the extracellular medium, and in doing so, play a critical role in the modulation of intracellular calcium levels. In this work, we have investigated whether inducers of PAH trigger any changes in the expression of PMCA proteins in PASMCs.Analysis of RNA expression levels for PMCA genes has revealed that treatment of PASMCs with PDGF results in a significant increase in the level of the RNA encoding for the protein PMCA1. Interestingly, PMCA1 RNA levels were also elevated in lungs of rats with monocrotaline-induced PAH. No changes were observed in the RNA levels for PMCA4, the other major PMCA isoform expressed in PASMCs. Although previous studies on the regulation of PMCA1 gene expression have identified functional binding sites for the transcription factors NFAT in the PMCA1 promoter region, we show here that PDGF-mediated upregulation of PMCA1 transcriptional expression is independent of activation of the calcineurin/ NFAT signalling pathway.Our results suggest the involvement of PMCA1 in PASMC deregulation during PAH, although determination of the link between increased expression of PMCA1 and PAH requires further investigation. Introduction Genome wide association studies have identified Tribbles-1 (TRIB1) to be significantly associated with all major plasma lipid traits and as a risk factor for ischaemic heart disease and myocardial infarction. Studies in mice using Trib1 full body KO and liver-specific over-expression and KO models have shown that hepatic expression of TRIB1 reduces circulating lipids. Additionally, Trib1 has been implicated as a regulator of alternatively activated macrophages. However the potential interplay between hepatocytes, macrophages and Trib1 remain unexplored. MYELOID EXPRESSION OF TRIB1 REGULATES THE POLA...

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