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.
Hardin
Amy O
AO
Children's Foundation Research Center at Le Bonheur Children's Medical Center, Room 301 West Patient Tower, 50 North Dunlap, Memphis, TN 38103, USA.
Meals
Elizabeth A
EA
Yi
Taolin
T
Knapp
Katherine M
KM
English
B Keith
BK
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