Regulation of immature dendritic cell migration by RhoA guanine nucleotide exchange factor Arhgef5.
ABSTRACT There are a large number of Rho guanine nucleotide exchange factors, most of which have no known functions. Here, we carried out a short hairpin RNA-based functional screen of Rho-GEFs for their roles in leukocyte chemotaxis and identified Arhgef5 as an important factor in chemotaxis of a macrophage phage-like RAW264.7 cell line. Arhgef5 can strongly activate RhoA and RhoB and weakly RhoC and RhoG, but not Rac1, RhoQ, RhoD, or RhoV, in transfected human embryonic kidney 293 cells. In addition, Gbetagamma interacts with Arhgef5 and can stimulate Arhgef5-mediated activation of RhoA in an in vitro assay. In vivo roles of Arhgef5 were investigated using an Arhgef-5-null mouse line. Arhgef5 deficiency did not affect chemotaxis of mouse macrophages, T and B lymphocytes, and bone marrow-derived mature dendritic cells (DC), but it abrogated MIP1alpha-induced chemotaxis of immature DCs and impaired migration of DCs from the skin to lymph node. In addition, Arhgef5 deficiency attenuated allergic airway inflammation. Therefore, this study provides new insights into signaling mechanisms for DC migration regulation.
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ABSTRACT: The family Euphorbiaceae is widely distributed throughout both hemispheres and ranges in morphological form from large desert succulents to trees and even small herbaceous types. Many species contain a milky juice which is more or less toxic, especially for cold-blooded animals, and can produce a dermatitis similar to that from poison ivy. Separation procedures and characterization of the less polar fractions of the plant extracts have been widely described in the literature for their content in diterpene derivatives. In the continuing research on biologically active compounds from Euphorbiaceae, a series of studies on the isolation and structure elucidation of glyceroglycolipids (GGLs) and glycosphingolipids (GSLs) have been carried out in order to develop the novel medicinal resources from natural Euphorbiaceae products. Glyceroglycolipids are major constituents of the chloroplast membrane in the plant kingdom. Recently, glycolipids were found to possess antitumor-promoting activity while glyceroglycolipids isolated from Euphorbiaceae have shown an interesting anti-inflammatory activity in vivo. Glycosphingolipids are present at the outer layer of the lipid-bilayer in biological membranes and are thought to participate in antigen-antibody reactions and transmission of biologically informations. Sphingolipid breakdown products, sphingosine and lysosphingolipids, inhibit protein kinase C, a pivotal enzyme in cell regulation and signal transduction. Sphingolipids and lysosphingolipids affect significantly cellular responses and exhibit antitumor promoter activities in various mammalian cells. These molecules may function as endogenous modulators of cell function and possibly as second messengers.Mini Reviews in Medicinal Chemistry 09/2003; 3(5):425-37. · 2.53 Impact Factor
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ABSTRACT: Dendritic cells are specialized antigen-presenting cells, critical for initiating and regulating immune responses. Two new studies demonstrate the importance of coordinated cytoskeletal regulation for their normal function.Current Biology 12/2004; 14(22):R965-7. · 9.65 Impact Factor