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      Leukotriene B 4, an activation product of mast cells, is a chemoattractant for their progenitors

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          Abstract

          Mast cells are tissue-resident cells with important functions in allergy and inflammation. Pluripotential hematopoietic stem cells in the bone marrow give rise to committed mast cell progenitors that transit via the blood to tissues throughout the body, where they mature. Knowledge is limited about the factors that release mast cell progenitors from the bone marrow or recruit them to remote tissues. Mouse femoral bone marrow cells were cultured with IL-3 for 2 wk and a range of chemotactic agents were tested on the c-kit + population. Cells were remarkably refractory and no chemotaxis was induced by any chemokines tested. However, supernatants from activated mature mast cells induced pronounced chemotaxis, with the active principle identified as leukotriene (LT) B 4. Other activation products were inactive. LTB 4 was highly chemotactic for 2-wk-old cells, but not mature cells, correlating with a loss of mRNA for the LTB 4 receptor, BLT1. Immature cells also accumulated in vivo in response to intradermally injected LTB 4. Furthermore, LTB 4 was highly potent in attracting mast cell progenitors from freshly isolated bone marrow cell suspensions. Finally, LTB 4 was a potent chemoattractant for human cord blood–derived immature, but not mature, mast cells. These results suggest an autocrine role for LTB 4 in regulating tissue mast cell numbers.

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          Mast cells: a cellular link between autoantibodies and inflammatory arthritis.

          Previous studies have revealed that autoantibodies, complement components, and Fc receptors each participate in the pathogenesis of erosive arthritis in K/BxN mice. However, it is not known which cellular populations are responsive to these inflammatory signals. We find that two strains of mice deficient in mast cells, W/Wv and Sl/Sld, were resistant to development of joint inflammation and that susceptibility was restored in the W/Wv strain by mast cell engraftment. Thus, mast cells may function as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis.
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            Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes.

            Arachidonic acid is metabolised either by cyclooxygenases to produce prostaglandins and thromboxanes or by lipoxygenases to produce mono-, di- and trihydroxyeicosatetraenoic acids (HETEs). Polymorphonuclear leukocytes (PMNs) release HETEs, including mono- and dihydroxy fatty acids, when exposed to stimuli such as the calcium ionophore A23187 (refs 1, 2). The mono-HETEs are assumed to be of particular importance with respect to effects on leukocyte function because they have been shown to possess both chemotactic and chemokinetic activities towards PMNs and eosinophils. However, we have now shown that the chemokinetic and aggregating activities released from rat and human PMNs exposed to ionophore A23187 (ref. 5) are not due to the release of mono-HETEs but to that of 5, 12-di-HETE (leukotriene B). This compound is active over the concentration range 10 pg ml-1 to 5 ng ml-1.
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              Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment.

              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.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                20 June 2005
                : 201
                : 12
                : 1961-1971
                Affiliations
                [1 ]Leukocyte Biology Section, Biomedical Sciences Division, Faculty of Medicine, Imperial College London, South Kensington, London SW7 2AZ, England, UK
                [2 ]Department of Veterinary Clinical Studies, University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian, EH25 9RG, Scotland, UK
                Author notes

                CORRESPONDENCE Timothy J. Williams: tim.williams@ 123456imperial.ac.uk

                Article
                20042407
                10.1084/jem.20042407
                2212026
                15955837
                5e6f87b7-0d71-41ff-8935-ce24724f1872
                Copyright © 2005, The Rockefeller University Press
                History
                : 24 November 2004
                : 4 May 2005
                Categories
                Article

                Medicine
                Medicine

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