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Prepublished online as a Blood First Edition Paper on June 12, 2003; DOI 10.1182/blood-2002-11-3596. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-11-3596v1 102/7/2532    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 Smith, R. E. Articles by Harnett, M. M. Search for Related Content PubMed PubMed Citation Articles by Smith, R. E. Articles by Harnett, M. M. Related Collections Immunobiology Phagocytes Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 October 2003, Vol. 102, No. 7, pp. 2532-2540 IMMUNOBIOLOGY A novel MyD-1 (SIRP-1) signaling pathway that inhibits LPS-induced TNF production by monocytes Rosemary E. Smith, Vanshree Patel, Sandra D. Seatter, Maureen R. Deehan, Marion H. Brown, Gareth P. Brooke, Helen S. Goodridge, Christopher J. Howard, Kevin P. Rigley, William Harnett, and Margaret M. Harnett From the Edward Jenner Institute for Vaccine Research and the Institute of Animal Health, Compton, Newbury, Berkshire, United Kingdom; the Division of Immunology, Infection and Inflammation, University of Glasgow; the Department of Immunology, University of Strathclyde, United Kingdom; and the Sir William Dunn School of Pathology, Oxford, United Kingdom. MyD-1 (CD172) is a member of the family of signal regulatory phosphatase (SIRP) binding proteins, which is expressed on human CD14+ monocytes and dendritic cells. We now show a novel role for MyD-1 in the regulation of the innate immune system by pathogen products such as lipopolysaccharide (LPS), purified protein derivative (PPD), and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on peripheral blood mononuclear cells (PBMCs) inhibits tumor necrosis factor alpha (TNF) secretion but has no effect on other cytokines induced in response to each of these products. In an attempt to understand the molecular mechanisms underlying this surprisingly selective effect we investigated signal transduction pathways coupled to MyD-1. Ligation of the SIRP was found to recruit the tyrosine phosphatase SHP-2 and promote sequential activation of phosphatidylinositol (PI) 3-kinase, phospholipase D, and sphingosine kinase. Inhibition of LPS-induced TNF secretion by MyD-1 appears to be mediated by this pathway, as the PI 3-kinase inhibitor wortmannin restores normal LPS-driven TNF secretion. MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNF production and consequent inflammatory disease. (Blood. 2003;102:2532-2540) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: X.-N. Kong, H.-X. Yan, L. Chen, L.-W. Dong, W. Yang, Q. Liu, L.-X. Yu, D.-D. Huang, S.-Q. Liu, H. Liu, et al. LPS-induced down-regulation of signal regulatory protein {alpha} contributes to innate immune activation in macrophages J. Exp. Med., October 29, 2007; 204(11): 2719 - 2731. [Abstract] [Full Text] [PDF] M. H. Lahoud, A. I. Proietto, K. H. Gartlan, S. Kitsoulis, J. Curtis, J. Wettenhall, M. Sofi, C. Daunt, M. O'Keeffe, I. Caminschi, et al. 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