THE PROTEIN-TYROSINE-PHOSPHATASE SHP-1 REGULATES INTEGRIN-MEDIATED ADHESION OF MACROPHAGES

The Src homology 2 domain phosphatase-l (SHP-1) is a tyrosine phosphat ase containing two amino-terminal SH2 domains and is expressed primari ly by hematopoietic-derived cells [1]. The viable motheaten (Hcph(me-v )) mutant mice (me(v)) suffer from progressive inflammation due to a d eficiency of SHP-1 enzyme activity [2,3] and die at 3-4 months of age from macrophage and neutrophil accumulation in the lung [4]. The mecha nism by which SHP-1 deficiency leads to inflammation is unknown. We fo und that macrophages from me(v) mice adhered and spread to a greater e xtent than normal macrophages through alpha m beta 2 integrin-mediated contacts. Whereas macrophages deficient in the transmembrane tyrosine phosphatase CD45 (CD45(-/-)) spontaneously detached from alpha m beta 5 integrin contacts [5], cells deficient in both CD45 and SHP-1 did n ot. In SHP-1-deficient macrophages there was a 10-15-fold increase in D-3 phospholipid products of phosphatidylinositol (PI) 3-kinase. Conco mitantly, there was a 2-5-fold increase in membrane-associated PI 3-ki nase activity in mev macrophages relative to normal macrophages. Treat ment of macrophages with the PI 3-kinase inhibitors wortmannin or LY29 4002 resulted in a dramatic detachment of cells, indicating that PI 3- kinase activity is required for adhesion. These data demonstrate that SHP-1 is necessary for detachment from alpha m beta 2 integrin-mediate d contacts in primary macrophages and suggest that a defect in this pa thway may contribute to inflammatory disease.