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author:("Kong, xiamen")
1.  BVT.2733, a Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, Attenuates Obesity and Inflammation in Diet-Induced Obese Mice 
PLoS ONE  2012;7(7):e40056.
Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is being pursued as a new therapeutic approach for the treatment of obesity and metabolic syndrome. Therefore, there is an urgent need to determine the effect of 11β-HSD1 inhibitor, which suppresses glucocorticoid action, on adipose tissue inflammation. The purpose of the present study was to examine the effect of BVT.2733, a selective 11β-HSD1 inhibitor, on expression of pro-inflammatory mediators and macrophage infiltration in adipose tissue in C57BL/6J mice.
Methodology/Principal Findings
C57BL/6J mice were fed with a normal chow diet (NC) or high fat diet (HFD). HFD treated mice were then administrated with BVT.2733 (HFD+BVT) or vehicle (HFD) for four weeks. Mice receiving BVT.2733 treatment exhibited decreased body weight and enhanced glucose tolerance and insulin sensitivity compared to control mice. BVT.2733 also down-regulated the expression of inflammation-related genes including monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α) and the number of infiltrated macrophages within the adipose tissue in vivo. Pharmacological inhibition of 11β-HSD1 and RNA interference against 11β-HSD1 reduced the mRNA levels of MCP-1 and interleukin-6 (IL-6) in cultured J774A.1 macrophages and 3T3-L1 preadipocyte in vitro.
These results suggest that BVT.2733 treatment could not only decrease body weight and improve metabolic homeostasis, but also suppress the inflammation of adipose tissue in diet-induced obese mice. 11β-HSD1 may be a very promising therapeutic target for obesity and associated disease.
PMCID: PMC3388048  PMID: 22768329
2.  SIRT1 links CIITA deacetylation to MHC II activation 
Nucleic Acids Research  2011;39(22):9549-9558.
Antigen-dependent stimulation of T cells plays a critical role in adaptive immunity and host defense. Activation of major histocompatibility complex II (MHC II) molecules, dictated by Class II transactivator (CIITA), is considered a pivotal step in this process. The mechanism underlying differential regulation of CIITA activity by the post-translational modification machinery (PTM) and its implications are not clearly appreciated. Here, we report that SIRT1, a type III deacetylase, interacts with and deacetylates CIITA. SIRT1 activation augments MHC II transcription by shielding CIITA from proteasomal degradation and promoting nuclear accumulation and target binding of CIITA. In contrast, depletion of SIRT1 upregulates CIITA acetylation and attenuates its activity. Nicotinamide phosphoribosyltransferase (NAMPT) that synthesizes NAD+ required for SIRT1 activation exerts similar effects on CIITA activity. Two different types of stress stimuli, hypobaric hypoxia and oxidized low-density lipoprotein (oxLDL), induce the acetylation of CIITA and suppress its activity by inhibiting the SIRT1 expression and activity. Thus, our data link SIRT1-mediated deacetylation of CIITA to MHC II transactivation in macrophages and highlight a novel strategy stress cues may employ to manipulate host adaptive immune system.
PMCID: PMC3239213  PMID: 21890893
3.  Regulating the Activity of Class II Transactivator by Posttranslational Modifications: Exploring the Possibilities▿  
Molecular and Cellular Biology  2009;29(21):5639-5644.
First identified as the master regulator of major histocompatibility complex II transcription, class II transactivator (CIITA) has since been implicated in a host of pathologies by modulating the transcription of multiple different genes. How CIITA caters to cell- and tissue-specific transcriptional needs is hotly debated and investigated. One of the possible mechanisms underlying spatiotemporal control of CIITA transcriptional activity is the posttranslational modification (PTM) machinery that refines certain amino acid residues of CIITA and hence alters its activity in response to specific cellular and environmental cues. This review discusses our current understanding of the PTM map of CIITA, how these modifications fine-tune its activity, and how the study of this area may lead to potential therapeutic strategies.
PMCID: PMC2772741  PMID: 19720744
4.  RFXB and its splice variant RFXBSV mediate the antagonism between IFNγ and TGFβ on COL1A2 transcription in vascular smooth muscle cells 
Nucleic Acids Research  2009;37(13):4393-4406.
Cytokines secreted by infiltrating immune cells during atherogenesis modulate vascular remodeling. One exemplary event is the antagonism between transformed growth factor (TGF-β) and interferon gamma (IFN-γ) on the transcriptional control of type I collagen gene (COL1A2). Previously we have reported that IFN-γ up-regulates regulatory factor for X-box B (RFXB) to repress collagen transcription while down-regulates the expression of RFXBSV, a splice variant of RFXB that blocks collagen repression in fibroblasts. Here we demonstrate that TGF-β abrogated COL1A2 repression by IFN-γ through altering the relative expression of RFXB and RFXBSV. Unlike RFXB, RFXBSV did not bind to the collagen promoter and competed with RFXB for the co-repressor histone deacetylase 2 (HDAC2), limiting HDAC2 recruitment to the collagen transcription start site as evidenced by chromatin immunoprecipitation assays. Over-expression of RFXB by lentiviral infection in HASMCs enhanced HDAC2 enlistment, promoted histone deacetylation surrounding the collagen site by IFN-γ, and blocked the TGF-β antagonism, a pattern reversed by RFXBSV infection. On the contrary, silencing of RFXB, but not both RFXB and RFXBSV, expression promoted the TGF-β antagonism. Thus, we have identified a novel mechanism whereby TGF-β antagonizes the IFN-γ repression of collagen transcription in HASMCs and as such provided new insights into antiatherogenic strategies.
PMCID: PMC2715248  PMID: 19465385

Results 1-4 (4)