SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages.
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.
Children's Foundation Research Center at Le Bonheur Children's Medical Center, Room 301 West Patient Tower, 50 North Dunlap, Memphis, TN 38103, USA.
Amy O
AO
Hardin
Elizabeth A
EA
Meals
Taolin
T
Yi
Katherine M
KM
Knapp
B Keith
BK
English
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C496619:Vav1 protein, mouse; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D013752:Tetracycline