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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1145-1150. Prepublished online as a Blood First Edition Paper on April 18, 2006; DOI 10.1182/blood-2005-12-012815. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2005-12-012815v1 108/4/1145    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tomkowicz, B. Articles by Collman, R. G. Search for Related Content PubMed PubMed Citation Articles by Tomkowicz, B. Articles by Collman, R. G. Related Collections Immunobiology Phagocytes Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS The Src kinase Lyn is required for CCR5 signaling in response to MIP-1 and R5 HIV-1 gp120 in human macrophages Brian Tomkowicz, Chuhee Lee, Vipa Ravyn, Ricky Cheung, Andrzej Ptasznik, and Ronald G. Collman From the Divisions of Pulmonary, Allergy and Critical Care and Hematology/Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia. CCR5 is a receptor for several chemokines and the entry coreceptor used by macrophage-tropic (R5) strains of HIV-1. In addition to supporting viral entry, CCR5 ligation by the HIV-1 envelope glycoprotein 120 (gp120) can activate intracellular signals in macrophages and trigger inflammatory mediator release. Using a combination of in vitro kinase assay, Western blotting for phospho-specific proteins, pharmacologic inhibition, CCR5 knockout (CCR532) cells, and kinase-specific blocking peptide, we show for the first time that signaling through CCR5 in primary human macrophages is linked to the Src kinase Lyn. Stimulation of human monocyte-derived macrophages with either HIV-1 gp120 or MIP-1 results in the CCR5-mediated activation of Lyn and the concomitant Lyn-dependent activation of the mitogen-activated protein (MAP) kinase ERK-1/2. Furthermore, activation of the CCR5/Lyn/ERK-1/2 pathway is responsible for gp120-triggered production of TNF- by macrophages, which is believed to contribute to HIV-1 pathogenesis. Thus, Lyn kinase may play an important role both in normal CCR5 function in macrophages and in AIDS pathogenesis in syndromes such as AIDS dementia where HIV-1 gp120 contributes to inappropriate macrophage activation, mediator production, and secondary injury. 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