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Samuel C. Silverstein, Ph.D. John C. Dalton Professor of Physiology and Cellular Biophysics E-mail: scs3@columbia.edu Tel: (212) 305-3546 Office: PI 11-444 Fax: (212) 305-5775 |
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CURRENT RESEARCH STRUCTURE AND FUNCTION OF POLYMORPHONUCLEAR (PMN), MONONUCLEAR PHAGOCYTES, LYMPHOCYTES, PLATELETS AND ENDOTHELIAL CELLS (EC) IN INNATE IMMUNTY AND DISEASES. My colleagues and I study the structure and functions of polymorphonuclear (PMN) and mononuclear phagocytes, lymphocytes, platelets and endothelial cells (EC) in innate immunity, in diseases associated with chronic inflammation such as atherosclerosis, Alzheimer's disease, and prion diseases; and in host defense against infectious micro-organisms including HIV. Studies are underway in five areas,two of which are described below. 1. Trans-endothelial migration of PMN and monocytes: Using mono-layers of cultured EC we have found that chemoattractant-stimulated PMN secrete a substance(s) that signals a rise in EC calcium and that this rise in EC calcium activates myosin light chain kinase (MLCK) and loosens EC junctions. Agents that block this rise in EC calcium, or that block MLCK, inhibit trans-endothelial movement of PMN. We are characterizing these PMN secretory product(s), and are testing the hypothesis that each leukocyte type secretes a different product that signals opening of EC junctions, and that EC express specific receptors for each of these products. 2. Effects of extracellular matrix proteins on PMN chemotaxis: In studying chemoattractant-stimulated PMN migration through three-dimensional gels composed of extracellular matrix proteins we discovered that both the identity of the chemoattractant and of the proteins in the matrix determine whether PMN migrate or become sessile. PMN migrate through fibrin gels in response to a gradient of leukotriene B4 (LTB4). In contrast, PMN do not migrate through fibrin gels in response to a gradient of formyl-methionyl-leucyl-phenylalanine (fMLP). Both chemoattractants stimulate PMN to migrate through gels composed of collagen I or IV. Further studies showed that fMLP activates alpha 5-beta1 integrins while LTB4 does not. Antibodies that block alpha 5-beta 1 integrins reverse the inhibitory effect of fibrin on migration of fMLP-stimulated PMN, but have no effect on the capacity of LTB4-stimulated PMN to migrate through fibrin gels. These findings suggest that specific chemoattractants and chemokines instruct leukocytes to stop or continue to migrate when they encounter ligands displayed on specific matrix and/or cell surface proteins. Studies are in progress to identify the intracellular signaling pathways that mediate cessation of migration. 3. Roles of scavenger receptors of mononuclear phagocytes and of EC in atherosclerosis, Alzheimer's disease, prion diseases and sepsis caused by gram positive bacteria. 4. Inhibitory effect of gemfibrozil on intracellular growth of Legionella pneumophila and Mycobacterium tuberculosis. 5. Mechanisms of HIV infection in humanized SCID mice. SELECTED PUBLICATIONS Li, Y., Karlin, A., Loike, J.D., and Silverstein, S.C. 2004. Determination of the critical concentration of neutrophils required to block bacterial growth in tissues. J Exp Med. 200(5):613-22. Loike, J.D., Shabtai, D.Y., Neuhut, R., Malitzky, S., Lu, E., Husemann, J., Goldberg, I.J., and Silverstein, S.C. 2004 Statin inhibition of Fc receptor-mediated phagocytosis by macrophages is modulated by cell activation and cholesterol. Arterioscler Thromb Vasc Biol. (11):2051-6. Wyss-Coray , T., Loike, J.D., Brionne, T.C., Lu, E., Anankov, R., Yan, F., Silverstein, S.C., and Husemann, J. 2003. Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Husemann, J., Loike, J.D., Anankov, R., Febbraio, M., Silverstein, S.C. 2002. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia. (2):195-205. Review Li, Y., Karlin, A., Loike, J.D., Silverstein, S.C. 2002. A critical concentration of neutrophils is required for effective bacterial killing in suspension. Proc Natl Acad Sci U S A. (12):8289-94. Berger, M., Budhu, S., Lu, E., Li, Y., Loike, D., Silverstein, S.C., Loike, J.D. 2002. Different G(i)-coupled chemoattractant receptors signal qualitatively different functions in human neutrophils. J Leukoc Biol. May;71(5):798-806. |
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