IntroductionIn multiple myeloma (MM), the growth of neoplastic plasma cells is directly regulated by microenvironmental factors in the bone marrow. 1 Of these, neoangiogenesis is thought to have a governing role in MM pathogenesis and progression, indicated by increased bone marrow microvascular density (MVD) in patients that is positively correlated with disease activity and by increased expression of angiogenic factors. [2][3][4][5][6] In fact, increased MVD in myeloma is thought to be largely driven by vascular endothelial growth factor (VEGF), which is secreted by MM and stromal cells in the marrow; these cells also express the receptors for VEGF, including VEGF receptor-2 (kinase insert domain-containing receptor/fetal liver kinase-1 [KDR]). [7][8][9] The production of VEGF by both cell types is increased by interleukin-6 (IL-6), which is produced by stromal cells and provides the survival signal for MM cells; VEGF in turn stimulates production of IL-6 and tumor growth. 10 Targeting of angiogenesis by thalidomide [11][12][13][14] and its more potent immunomodulatory derivatives (IMiDs; Celgene, Warren, NJ) 15,16 is an effective therapeutic strategy against MM in newly diagnosed, relapsed, and refractory patients. Recent data showing a proangiogenic gene expression profile within bone marrow endothelial cells (ECs) of patients with MM suggest that these ECs had undergone an angiogenic switch 17 similar to that observed in solid tumors. 18,19 However, the role of neovascularization in mechanisms involved in MM growth and dissemination requires further elucidation. From the clinical perspective, since MVD may not reflect real-time vascular activity in the marrow, and since MVD determination requires a bone marrow biopsy, a less invasive method that can assess dynamic changes in angiogenesis is needed for gaining insight into the natural course of MM and improving patient management.Growth and dissemination of tumors is supported by neovascularization (new vessel formation), which involves vasculogenesis (de novo tube formation analogous to prenatal vascular development) and angiogenesis (sprouting of new capillary vessels from pre-existing vasculature). Exciting new data show that tumor neovascularization involves recruitment of endothelial progenitor cells (EPCs) from bone marrow and, conversely, that inhibition of EPC recruitment inhibits tumor growth, thus establishing the significance of EPCs in tumor progression. [20][21][22][23][24] Consequently, inhibition of EPCs is a promising treatment modality with benefit both for solid and for liquid tumors. New research also has shown that within human bone marrow and cord blood, EPCs are derived from pluripotential stem cells and from more differentiated hemangioblasts, which are the precursors for both hematopoietic cells and 24 Increased mobilization of CECs and EPCs has been associated with cancer, vascular injury and, in patients with lymphoma, poor prognosis. [36][37][38] In MM, EPCs in peripheral blood have not been characterized, and their role in diseas...
Microsomal triglyceride transfer protein (MTP) is needed to assemble chylomicrons in the endoplasmic reticulum (ER) of enterocytes. We explored the role of an ER stress protein, inositol-requiring enzyme 1beta (IRE1beta), in regulating this process. High-cholesterol and high-fat diets decreased intestinal IRE1beta mRNA in wild-type mice. Ire1b(-/-) mice fed high-cholesterol and high-fat diets developed more pronounced hyperlipidemia because these mice secreted more chylomicrons and expressed more intestinal MTP, though not hepatic MTP, than wild-type mice did. Chylomicron secretion and MTP expression also were increased in primary enterocytes isolated from cholesterol-fed Ire1b(-/-) mice. There was no correlation between ER stress and MTP expression. Instead, cell culture studies revealed that IRE1beta, but not its ubiquitous homolog IRE1alpha, decreased MTP mRNA through increased posttranscriptional degradation. Conversely, knockdown of IRE1beta enhanced MTP expression. These studies show that IRE1beta plays a role in regulating MTP and in chylomicron production.
Summary To understand how the Bcl6 transcriptional repressor functions in the immune system we disrupted its RD2 repression domain in mice. Bcl6RD2MUT mice exhibit a complete loss of GC formation but retain normal extrafollicular responses. Bcl6RD2MUT antigen-engaged B-cells migrate to the interfollicular zone and interact with cognate T helper cells. However, these cells fail to complete early GC-commitment differentiation and coalesce as nascent GC aggregates. Bcl6 directly binds and represses trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B-cell migration and may contribute to GC failure in Bcl6RD2MUT mice. The development of functional GC-TFH cells was partially impaired in Bcl6RD2MUT mice. In contrast to Bcl6−/− mice, Bcl6RD2MUT animals experience no inflammatory disease or macrophage deregulation. These results reveal an essential role for RD2 repression in early GC commitment and striking biochemical specificity in Bcl6 control of humoral and innate immune-cell phenotypes.
Microsomal triglyceride transfer protein is a target to lower plasma lipids and to reduce inflammation in certain immune disorders. More knowledge is required, however, regarding its regulation and its role in the biosynthesis of apoB-containing lipoproteins and CD1d.
Objective-Our aim was to elucidate mechanisms involved in the acquisition of lipid transport properties during enterocyte differentiation. Methods and Results-We show that lipid mobilization via apolipoprotein B lipoproteins is dependent on the expression of microsomal triglyceride transfer protein (MTP) during differentiation of Caco-2 cells into enterocyte-like cells. Mechanistic studies showed that binding of the nuclear receptor family 2 group F member 1 (NR2F1) to the DR1 element in the MTTP promoter suppresses MTTP expression in undifferentiated cells. During cellular differentiation, NR2F1 expression and its binding to MTTP promoter decline and MTP induction ensues. Moreover, undifferentiated cells express inositol-requiring enzyme 1 (IRE1), a protein that posttranscriptionally degrades MTP mRNA, and its expression substantially decreases during differentiation, contributing to MTP induction. Immunohistochemical studies revealed a significant negative relationship between the expressions of MTP and NR2F1/IRE1 in undifferentiated and differentiated Caco-2 cells, as well as in crypt-villus and jejunum-colon axes of mouse intestine. ntestinal crypts harbor stem/progenitor cells that divide, migrate, and differentiate into enterocytes 1 and absorb dietary constituents such as carbohydrates and lipids. Expression of carbohydrate hydrolyzing enzymes during enterocyte differentiation is dependent on Cdx2. 2 Lipid absorption depends on the biosynthesis of triglyceride-rich lipoproteins that requires apolipoprotein B (apoB), a structural protein, and microsomal triglyceride transfer protein (MTP), an endoplasmic reticulum resident chaperone. 3,4 Mechanisms promoting induction of apoB lipoprotein biogenesis and lipid absorption during differentiation of enterocytes are unknown. Conclusion-WeHuman colon carcinoma Caco-2 cells are used extensively to study cellular differentiation. 5-7 Undifferentiated Caco-2 cells do not synthesize or secrete apoB lipoproteins. However, during culture these cells spontaneously differentiate into enterocyte-like cells and produce chylomicron-size apoB containing lipoproteins when supplemented with oleic acid. 6,8 -14 We report that 2 proteins, nuclear receptor family 2 group F member 1 (NR2F1) and inositol-requiring enzyme 1 (IRE1), prevent MTP expression at transcriptional and posttranscriptional levels in undifferentiated intestinal cells and restrict apoB lipoprotein biosynthesis. Materials and MethodsChemicals and reagents, primary antibodies, and secondary antibodies were purchased from Sigma, Santa Cruz Biotechnology, and Invitrogen, respectively. Caco-2 cells were allowed to differentiate on transwells and studied for the secretion of apoB lipoproteins. These cells were also infected with adenoviruses expressing human MTP or transfected with various plasmids or siRNA. For Supplemental Methods, please see http://atvb.ahajournals.org. Experiments were performed in triplicate and repeated at least twice. Data are presented as meanϮSEM. Statistical significances (PϽ0.05) we...
This study implies that S1PR2, as a critical receptor in macrophage, impairs phagocytosis and antimicrobial defense in the pathogenesis of sepsis. Interventions targeting S1PR2 signaling may serve as promising therapeutic approaches for sepsis.
HepaticapolipoproteinB(apoB)lipoproteinproductionismetabolicallyregulatedviathephosphoinositide 3-kinase cascade; however, the role of the key negative regulator of this pathway, the tumor suppressor phosphatase with tensin homology (PTEN), is unknown. Here, we demonstrate that hepatic protein levels of apoB100 and microsomal triglyceride transfer protein (MTP) are significantly down-regulated (73% and 36%, respectively) in the liver of PTEN liver-specific knockout (KO) mice, and this is accompanied by increased triglyceride (TG) accumulation and lipogenic gene expression, and reduced hepatic apoB secretion in freshly isolated hepatocytes. MTP protein mass and lipid transfer activity were also significantly reduced in liver of PTEN KO mice. Overexpression of the dominant negative mutant PTEN C/S124 (adenovirus expressing PTEN C/S mutant [AdPTENC/S]) possessing constitutive phospoinositide 3-kinase activity in HepG2 cells led to significant reductions in both secreted apoB100 and cellular MTP mass (76% and 34%, respectively), and increased messenger RNA (mRNA) levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Reduced apoB100 secretion induced by AdPTENC/S was associated with increased degradation of newly-synthesized cellular apoB100, in a lactacystin-sensitive manner, suggesting enhanced proteasomal degradation. AdPTENC/S also reduced apoB-lipoprotein production in McA-RH7777 and primary hamster hepatocytes. Our findings suggest a link between PTEN expression and hepatic production of apoB-containing lipoproteins. We postulate that perturbations in PTEN not only may influence hepatic insulin signaling and hepatic lipogenesis, but also may alter hepatic apoB-lipoprotein production and the MTP stability. On loss of PTEN activity, increased lipid substrate availability in the face of reduced hepatic lipoprotein production capacity can rapidly lead to hepatosteatosis and fatty liver.
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