Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL). This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic. On the other hand, CETP could also be anti-atherogenic, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.
In inflamed venules, neutrophils rolling on E-selectin induce integrin ␣ L  2 -dependent slow rolling on intercellular adhesion molecule-1 by activating Src family kinases (SFKs), DAP12 and Fc receptor-␥ (FcR␥), spleen tyrosine kinase (Syk), and p38. E-selectin signaling cooperates with chemokine signaling to recruit neutrophils into tissues. Previous studies identified P-selectin glycoprotein ligand-1 (PSGL-1) as the essential Eselectin ligand and Fgr as the only SFK that initiate signaling to slow rolling. In contrast, we found that E-selectin engagement of PSGL-1 or CD44 triggered slow rolling through a common, lipid raftdependent pathway that used the SFKs Hck and Lyn as well as Fgr. We identified the Tec kinase Bruton tyrosine kinase as a key signaling intermediate between Syk and p38. E-selectin engagement of PSGL-1 was dependent on its cytoplasmic domain to activate SFKs and slow rolling. Although recruiting phosphoinositide-3-kinase to the PSGL-1 cytoplasmic domain was reported to activate integrins, Eselectin-mediated slow rolling did not require phosphoinositide-3-kinase. Studies in mice confirmed the physiologic significance of these events for neutrophil slow rolling and recruitment during inflammation. Thus, E-selectin triggers common signals through distinct neutrophil glycoproteins to induce ␣ L  2 -dependent slow rolling. (Blood. 2010;116(3):485-494) IntroductionCirculating leukocytes enter inflamed tissues through sequential adhesive and signaling events. 1 Neutrophils first tether to and roll on P-and E-selectin expressed on activated endothelial cells. 2 They roll on P-selectin through interactions with P-selectin glycoprotein ligand-1 (PSGL-1) 3,4 and on E-selectin through interactions with PSGL-1, CD44, and E-selectin ligand-1. [5][6][7] Rolling neutrophils encounter immobilized chemokines that signal through G␣ i proteincoupled receptors. These signals activate integrins ␣ L  2 and ␣ M  2 to their high-affinity states, enabling interactions with intercellular adhesion molecule-1 (ICAM-1) that promote arrest, adhesion strengthening, intraluminal crawling, and transendothelial migration. 1 Importantly, E-selectin directly triggers signals in rolling neutrophils that cooperate with chemokine signals to maximize neutrophil recruitment during inflammation. 8 In autoperfused whole blood, neutrophils rolling on immobilized E-selectin activate ␣ L  2 to an intermediate-affinity state, which slows rolling on coimmobilized ICAM-1. 8 In vivo, neutrophils roll slowly on E-selectin expressed in tumor necrosis factor-␣ (TNF-␣)-stimulated postcapillary venules. 9 Injecting anti-␣ L  2 antibody increases rolling velocities, documenting the physiologic importance of integrins for slow rolling in vivo. 8,10 Integrin-dependent slow rolling prolongs transit times in inflamed venules 11 and enhances neutrophil recruitment. 8 In autoperfused whole blood, it was reported that integrinmediated slow rolling on E-selectin and ICAM-1 is eliminated in neutrophils lacking PSGL-1 but only marginally impaired in ne...
We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP ؊/؊ mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19 ؉ B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19 ؉ B-cell population and their progenitors recovered in an IL-6 ؊/؊ background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-␣ chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression. IntroductionAll hematopoietic cells develop from pluripotent hematopoietic stem cells (HSCs). Hematopoietic development proceeds in stages of decreasing lineage choices and decreasing capacity for selfrenewal of the progeny. HSCs feature a lack of all lineage markers (Lin Ϫ ) but express high levels of the receptor tyrosine kinase c-Kit (c-Kit hi ) and the surface protein Sca-1 (termed the LSK fraction). HSCs give rise to multipotent progenitors (MPPs), marked by a loss of self-renewal capacity, the ability to form either myeloid or lymphoid cells, and up-regulation of the Flk2/Flt3 receptor tyrosine kinase. 1 The earliest lymphoid-biased progenitors (ELPs) represent a subset of MPPs that can be resolved from all other progenitors on the basis of recombination activating gene 1 expression. 2 Lymphoid progenitors that develop from MPPs have reduced levels of c-Kit, display surface interleukin-7 receptor ␣ (IL-7R␣), and have other properties that define a population called common lymphoid progenitors (CLPs). 3 Hematopoiesis is normally a well-controlled system designed to replenish blood cells at a constant rate, such that the balance of lymphoid and myeloid cells is maintained. However, the rate of output of particular blood cell types can be altered by conditions such as leukemia, radiation, or acute inflammation. 4-11 One condition termed "emergency hematopoiesis," 12,13 is characterized by elevated production of myeloid cells, occurring during acute infections or acute allergic responses. The mechanism by which hematopoiesis is altered to elevate production of myeloid cells is not known. The consequence of emergency hematopoiesis is to increase circulating monocytes, granulocytes, and neutrophils, presumably present to fight infection.Interleukin-6 (IL-6) is a prominent cytokine produced during infectious disease (reviewed in...
CD73 is a GPI-anchored cell surface protein with ecto-5′-nucleotidase enzyme activity that plays a crucial role in adenosine production. While the roles of adenosine receptors (AR) on osteoblasts and osteoclasts have been unveiled to some extent, the roles of CD73 and CD73-generated adenosine in bone tissue are largely unknown. To address this issue, we first analyzed the bone phenotype of CD73-deficient (cd73−/−) mice. The mutant male mice showed osteopenia, with significant decreases of osteoblastic markers. Levels of osteoclastic markers were, however, comparable to those of wild type mice. A series of in vitro studies revealed that CD73 deficiency resulted in impairment in osteoblast differentiation but not in the number of osteoblast progenitors. In addition, over expression of CD73 on MC3T3-E1 cells resulted in enhanced osteoblastic differentiation. Moreover, MC3T3-E1 cells expressed adenosine A2A receptors (A2AAR) and A2B receptors (A2BAR) and expression of these receptors increased with osteoblastic differentiation. Enhanced expression of osteocalcin (OC) and bone sialoprotein (BSP) observed in MC3T3-E1 cells over expressing CD73 were suppressed by treatment with an A2BAR antagonist but not with an A2AAR antagonist. Collectively, our results indicate that CD73 generated adenosine positively regulates osteoblast differentiation via A2BAR signaling.
Src homology 2 domain-containing inositol 5-phosphatase (SHIP ؊/؊ ) animals display an age-related increase in interleukin-6 (IL-6), a decrease in B lymphopoiesis, and an elevation in myelopoiesis. We investigated the origin of the IL-6 production and show that it is largely produced by peritoneal and splenic macrophages. IL-6 production by these macrophages is not a direct result of the loss of SHIP: IL-6 production is not spontaneous, is absent from bone marrow-derived macrophages, declines with prolonged culture of
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