SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages |
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Authors: | Hardin Amy O Meals Elizabeth A Yi Taolin Knapp Katherine M English B Keith |
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Affiliation: | Children's Foundation Research Center at Le Bonheur Children's Medical Center, Room 301 West Patient Tower, 50 North Dunlap, Memphis, TN 38103, USA. |
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Abstract: | Several lines of evidence have suggested that protein tyrosine phosphatases, including CD45 and SHP-1, regulate macrophage activation. Macrophages from mice lacking SHP-1 (motheaten mice) are hyper-responsive to many stimuli, suggesting that SHP-1 may negatively regulate macrophage activation. Herein we report that the repressible/inducible over-expression of wild-type SHP-1 in a subclone of RAW 264.7 macrophages (RAW-TT10 cells) inhibited both TNF secretion and iNOS protein accumulation in response to stimulation with lipopolysaccharide (LPS) and recombinant murine interferon-gamma and led to diminished LPS-mediated tyrosine phosphorylation of vav1. In contrast, expression of a truncated SHP-1 construct previously shown to interfere with endogenous SHP-1 function modestly augmented LPS-mediated TNF and iNOS production and did not inhibit vav1 tyrosine phosphorylation. Taken together, these data provide the first direct evidence that SHP-1 inhibits macrophage activation by LPS and suggest that this effect may be mediated in part by dephosphorylation of vav1. |
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Keywords: | Tyrosine Macrophage TNF iNOS SHP-1 Cytokine Signal transduction Phosphatase Kinase |
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