Identification of an alternative short ARID5B isoform associated with B-ALL survival.

Utilizing RNA sequence (RNA-Seq) splice junction data from a cohort of 1841 B-cell acute lymphoblastic leukemia (B-ALL) patients we define transcriptionally distinct isoforms of ARID5B, a risk-associated gene identified in genome wide association studies (GWAS), which associate with disease survival. Short (S) and long (L) ARID5B transcripts, which differ in an encoded BAH-like chromatin interaction domain, show remarkable correlation to the isoform splicing pattern. Testing of the ARID5B proximal promoter of the S & L isoforms indicated that both are functionally independent in luciferase reporter assays.

regulates fatty acid metabolism and proliferation at the Pre-B cell stage during B cell development.

During B cell development in bone marrow, large precursor B cells (large Pre-B cells) proliferate rapidly, exit the cell cycle, and differentiate into non-proliferative (quiescent) small Pre-B cells. Dysregulation of this process may result in the failure to produce functional B cells and pose a risk of leukemic transformation. Here, we report that AT rich interacting domain 5B (), a B cell acute lymphoblastic leukemia (B-ALL) risk gene, regulates B cell development at the Pre-B stage.

Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia.

Objective: Adipose tissue is the largest endocrine organ. When activated by cancer cells, adipocytes secrete adipocytokines and release fatty acids, which are then transferred to cancer cells and used for structural and biochemical support. How this metabolic symbiosis between cancer cells and adipocytes affects skeletal muscle and thermogenesis during cancer cachexia is unknown.

Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production.

The lipopolysaccharide (LPS)-induced endocytosis of Toll-like receptor 4 (TLR4) is an essential step in the production of interferon-β (IFN-β), which activates the transcription of antiviral response genes by STAT1 phosphorylated at Tyr Here, we showed that STAT1 regulated proinflammatory cytokine production downstream of TLR4 endocytosis independently of IFN-β signaling and the key proinflammatory regulator NF-κB. In human macrophages, TLR4 endocytosis activated a noncanonical phosphorylation of STAT1 at Thr, which subsequently promoted the production of interleukin-6 (IL-6) and IL-12p40 through distinct mechanisms. STAT1 phosphorylated at Thr activated the expression of the gene encoding ARID5A, which stabilizes mRNA.

Feedback regulation of Arid5a and Ppar-γ2 maintains adipose tissue homeostasis.

Immune cells infiltrate adipose tissues and provide a framework to regulate energy homeostasis. However, the precise underlying mechanisms and signaling by which the immune system regulates energy homeostasis in metabolic tissues remain poorly understood. Here, we show that the AT-rich interactive domain 5A (Arid5a), a cytokine-induced nucleic acid binding protein, is important for the maintenance of adipose tissue homeostasis.

Regulatory T-Cells Mediate IFN-α-Induced Resistance against Antigen-Induced Arthritis.

Objective: CD4FoxP3CD25 regulatory T-cells (T) are important for preventing tissue destruction. Here, we investigate the role of T for protection against experimental arthritis by IFN-α.

Methods: Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP mice [allowing selective depletion of T by diphtheria toxin (DT)] and CD4-Cre IFNA1R flox/flox mice (devoid of IFNAR signaling in T-cells) earlier immunized with mBSA, with or without treatment with IFN-α or the indoleamine 2,3-dioxygenase (IDO)-metabolite kynurenine.

Arid5a stabilizes OX40 mRNA in murine CD4 T cells by recognizing a stem-loop structure in its 3'UTR.

AT-rich interactive domain-containing protein 5a (Arid5a) is an RNA-binding protein (RBP) required for autoimmunity via stabilization of interleukin-6 (Il6) and signal transducer and activator of transcription 3 (STAT3) mRNAs. However, the roles of Arid5a in Th17 cells and its association with autoimmunity remain unknown. Here, we show that the levels of Arid5a and OX40 are correlated in CD4 T cells under Th17 conditions in an IL-6-dependent manner.

Arid5a-deficient mice are highly resistant to bleomycin-induced lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are among the major causes of death worldwide due to acute inflammation in the lung. AT-rich interactive domain-containing 5a (Arid5a) is an RNA-binding protein involved in inflammatory autoimmune disease through post-transcriptional control of Il6, Stat3 and Tbx21 gene expression. We found that Arid5a-deficient mice were highly refractory to bleomycin (BLM)-induced lethality.

TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a.

The AT-rich interactive domain-containing protein 5a (Arid5a) plays a critical role in autoimmunity by regulating the half-life of Interleukin-6 (IL-6) mRNA. However, the signaling pathways underlying Arid5a-mediated regulation of IL-6 mRNA stability are largely uncharacterized. Here, we found that during the early phase of lipopolysaccharide (LPS) stimulation, NF-κB and an NF-κB-triggered IL-6-positive feedback loop activate Arid5a gene expression, increasing IL-6 expression via stabilization of the IL-6 mRNA.

Arid5a exacerbates IFN-γ-mediated septic shock by stabilizing T-bet mRNA.

Adenine-thymine (AT)-rich interactive domain containing protein 5a (Arid5a) is an RNA-binding protein that has been shown to play an important immune regulatory function via the stabilization of IL-6 and STAT3 mRNA. However, the role of Arid5a in the overwhelming and uncontrolled immune response that leads to septic shock is unknown. Here, we report that Arid5a-deficient mice are highly resistant to lipopolysaccharide (LPS)-induced endotoxic shock and secrete lower levels of major proinflammatory cytokines, including IFN-γ, IL-6, and TNF-α, than WT mice in response to LPS.

IDO1 and TGF-β Mediate Protective Effects of IFN-α in Antigen-Induced Arthritis.

IFN-α prevents Ag-induced arthritis (AIA), and in this study we investigated the role of IDO1 and TGF-β signaling for this anti-inflammatory property of IFN-α. Arthritis was induced by methylated BSA (mBSA) in mBSA-sensitized wild-type (WT), Ido1, or Ifnar mice, treated or not with IFN-α or the IDO1 product kynurenine (Kyn). Enzymatic IDO1 activity, TGF-β, and plasmacytoid dendritic cells (pDC) were neutralized by 1-methyltryptophan and Abs against TGF-β and pDC, respectively.

Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis.

Objective: Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis.

Methods: Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA.

Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.

Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis.

Type I IFN protects against antigen-induced arthritis.

Autoimmune diseases including rheumatoid arthritis (RA) involve immune reactions against specific antigens. The type I IFN system is suspected to promote autoimmunity in systemic lupus erythematosus, but may also dampen immune reactions in e.g.

Antioxidant activity and polyphenol content in edible wild fruits from Nepal.

Fifteen fruits commonly used by the ethnic population in Nepal were studied for the antioxidant activity and total polyphenol content (TPC). Among them, Terminalia bellirica, Terminalia chebula, Phyllanthus emblica and Spondias pinnata were the most potent antioxidants as compared with vitamin C based on the 1,1-diphenyl-2-picryl hydrazyl radical assay. These fruits also contained high TPCs.