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ABSTRACT: L-selectin mediates the initial tethering and rolling of lymphocytes in high endothelial venules. To study the transcriptional regulation of mouse L-selectin, we cloned 4.5 kb 5'-flanking sequences of the mouse sell. Luciferase analysis of serial 5'-deletion mutants showed that the first 285 bp was sufficient to drive high promoter activity in EL4 cells, but not in Sell-negative HeLa cells, suggesting that this fragment harbors the minimal mouse sell promoter and contains cis-elements for lymphocyte-specific expression. Site-directed mutagenesis and chromatin immunoprecipitation showed that Mzf1, Klf2, Sp1, Ets1, and Irf1 bind to and activate the mouse sell promoter. Over expression of these transcription factors in EL4 cells increased expression of sell mRNA. Silencing the expression of Sp1 by siRNA significantly decreased sell promoter activity in EL4 cells. We conclude that sell transcription is regulated by Mzf1, Klf2, Sp1, Ets1, and Irf1.
Biochimica et Biophysica Acta 12/2008; 1789(2):146-52. · 4.66 Impact Factor
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ABSTRACT: To study rolling of mouse neutrophils on E-selectin and ICAM-1 in an ex vivo flow chamber system.
The authors developed a small autoperfused flow chamber (20 x 200-microm cross section) that allows direct visualization of cells with and without fluorescent labeling and does not require recirculation of blood.
Neutrophils rolled on E-selectin alone, but were unable to interact with immobilized ICAM-1. When ICAM-1 was co-immobilized with E-selectin, the number of cells that rolled was doubled, but no significant firm adhesion was observed. This phenomenon was specific for E-selectin, and no enhancement of rolling was observed when P-selectin was immobilized with ICAM-1. The increased neutrophil rolling seen on E-selectin and ICAM-1 substrates required beta2 integrins. Treating mice with antibodies to the beta2 integrins LFA-1 and Mac-1 showed that LFA-1 was primarily responsible for mediating rolling on ICAM-1 in this model. Increased rolling on E-selectin and ICAM-1 was significantly reduced following administration of a specific p38 mitogen-activated protein kinase (MAPK) inhibitor.
The data show that neutrophil rolling on E-selectin leads to partial activation of LFA-1, enabling LFA-1-dependent rolling on ICAM-1. This mechanism is likely to amplify and accelerate neutrophil recruitment in inflammation.
Microcirculation 04/2006; 13(2):99-109. · 2.57 Impact Factor
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ABSTRACT: L-selectin (CD62L) is an adhesion molecule expressed on most leukocytes. This article describes recent findings of L-selectin's role in the recruitment of T cells to sites of inflammation and its contribution to the acquisition of immunologic memory. We discuss the regulation of L-selectin expression during and after the activation of T cells and its physiological function during the course of inflammation. Different disease models and current approaches for drug development are reviewed.Section editors:Giora Feuerstein – Translational Medicine, Wyeth Research, USAJames Hershey – Department of Molecular Endocrinology, Merck Research Laboratories, USA
Drug Discovery Today: Therapeutic Strategies.
