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Prepublished online as a Blood First Edition Paper on June 12, 2003; DOI 10.1182/blood-2002-11-3596.
Submitted December 2, 2002
Accepted May 28, 2003
A novel MyD-1 (SIRP ) signalling 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*
Edward Jenner Institute for Vaccine Research, Newbury, Berkshire, United Kingdom
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, Strathclyde, United Kingdom
Sir William Dunn School of Pathology, Oxford, Oxon, United Kingdom
Institute of Animal Health, Newbury, Berkshire, United Kingdom
Department of Immunology, University of Strathclyde, Glasgow, Strathclyde, United Kingdom
* Corresponding author; email: M.Harnett{at}bio.gla.ac.uk.
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, LPS, PPD and Zymosan. Specifically, we demonstrate that ligation of MyD-1 on PBMC inhibits 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 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 signalling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNF production and consequent inflammatory disease.
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