Leukotriene B4 (LTB4) was originally described as a potent lipid myeloid cell chemoattractant, rapidly generated from innate immune cells, that activates leukocytes through the G protein-coupled receptor BLT1. We report here that BLT1 is expressed on effector CD4+ T cells generated in vitro as well as in vivo when effector T cells migrate out of the lymphoid compartment and are recruited into peripheral tissues. BLT1 mediated LTB4-induced T helper type 1 (T(H)1) and T(H)2 cell chemotaxis and firm adhesion to endothelial cells under flow, as well as early CD4+ and CD8+ T cell recruitment into the airway in an asthma model. Our findings show that the LTB4-BLT1 pathway is involved in linking early immune system activation and early effector T cell recruitment.
Abstract-Our goal was to identify functionally important subpopulations within the heterogenous group of endothelial progenitor cells (EPC). Fluorescence-activated cell sorter analysis of CD133 ϩ progenitor cells revealed the presence of CD34 ϩ and CD34 Ϫ subpopulations. CD34 Ϫ /133 ϩ progenitors differentiate into CD34 ϩ /133 ϩ EPC, adhere more potently than these in response to SDF-1, and rapidly home to sites of limb ischemia in human volunteers. In human coronary atherectomy samples, fewer CD34Ϫ /133 ϩ than CD34 ϩ /133 ϩ EPC are present in stable plaques, whereas cell numbers increase with a reversion of the ratio in unstable lesions. In CD34 Ϫ /133 ϩ EPC-injected nude mice, more transplanted cells coexpressing endothelial markers home to carotid artery lesion endothelium than in CD34 ϩ /133 ϩ -injected mice. In the former, lesions were smaller and reendothelialization higher than in the latter. We identified a new CD34 Ϫ /133 ϩ EPC subpopulation, which is apparently a precursor of "classical" CD34 ϩ /133 ϩ EPC, and functionally more potent than these with respect to homing and vascular repair. (Circ Res. 2006;98:e20-e25.)
Integrin-linked kinase (ILK) is a phosphoinositide 3-kinase-dependent serine/threonine kinase that interacts with  integrins. Here we show that endothelial cell (EC)-specific deletion of ILK in mice confers placental insufficiency with decreased labyrinthine vascularization, yielding no viable offspring. Deletion of ILK in zebra fish using antisense morpholino oligonucleotides results in marked patterning abnormalities of the vasculature and is similarly lethal. To dissect potential mechanisms responsible for these phenotypes, we performed ex vivo deletion of ILK from purified EC of adult mice. We observed downregulation of the active-conformation of 1 integrins with a striking increase in EC apoptosis associated with activation of caspase 9. There was also reduced phosphorylation of the ILK kinase substrate, Akt. However, phenotypic rescue of ILK-deficient EC by wild-type ILK, but not by a constitutively active mutant of Akt, suggests regulation of EC survival by ILK in an Akt-independent manner. Thus, endothelial ILK plays a critical role in vascular development through integrin-matrix interactions and EC survival. These data have important implications for both physiological and pathological angiogenesis.
Chemokines such as the monocyte chemol attractant protein-1 (MCP-1) convert monocyte rolling to firm arrest under physiological flow conditions via integrin activation and simultaneously activate phosphoinositide 3-kinase (PI3K). Here we used adenoviral gene transfer and biochemical inhibitors to manipulate PI3K-dependent pathways in human monocytes. In in vitro lipid kinase assays from purified human monocytes, we showed that MCP-1 activates the "classical" PI3K␣ pathway and not PI3K␥, a PI3K isoform thought to be activated only by the ␥ complex of heterotrimeric G proteins. The activity of PI3K␣ in purified human monocytes was evident within 30 s. MCP-1-induced monocyte arrest was significantly inhibited both by wortmannin (n ؍ 4; p < 0.01) and LY294002 (n ؍ 4; p < 0.01) with restoration of the rolling phenotype (p < 0.05 for both inhibitors, compared with rolling of control monocytes after MCP-1 treatment). To test the hypothesis that activation of PI3K is sufficient to induce monocyte adhesion, we transduced the monocytic THP-1 cell line with a recombinant adenovirus (Ad) carrying a constitutively active mutant of PI3K (Ad.BD110). We examined the ability of these cells to adhere to human vascular endothelium (HUVEC) transduced with adenoviruses carrying E-selectin, intercellular adhesion molecule-1 (ICAM-1), and VCAM-1. Under flow conditions, ICAM-1-and VCAM-1-dependent firm adhesion of Ad.BD110-transduced THP-1 cells was enhanced compared with THP-1 cells infected with control Ad (n ؍ 4; p < 0.01 for both). Adhesion augmented by constitutive PI3K activation was entirely abrogated by pretreatment with wortmannin (n ؍ 3; p < 0.01). In contrast, a constitutively active Akt construct had no effect on THP-1 adhesion (n ؍ 3; p ؍ NS). We conclude that PI3K activation is necessary and sufficient to enhance monocytic adhesion under physiological flow conditions. BD110-expressing THP-1 cells should provide a useful tool for identifying the signaling pathways downstream of PI3K that are necessary for monocyte recruitment relevant to a variety of human vascular pathologies.In vitro and in vivo models suggest a role for chemokines in a variety of inflammatory pathologies, including asthma, arthritis, and atherosclerosis. As chemoattractants, chemokines play an important role in the directional migration of leukocytes through tissues. Recent data have also underscored the importance of chemokines in enhancing the avidity of leukocyte integrins for locally expressed adhesion molecules. Under physiological flow conditions such as seen in the bloodstream, chemokines can induce the rapid conversion of lymphocyte (1) or monocyte (2) tethering (rolling) to firm adhesion via integrin activation. These data speak to an important role for chemokines in the initial step of leukocyte infiltration of the endothelium, which is then followed by transmigration into the surrounding tissues. However, the pathways by which chemokines activate leukocytes, markedly enhancing leukocyte firm adhesion over the course of seconds, r...
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