SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages

Biochem Biophys Res Commun. 2006 Apr 7;342(2):547-55. doi: 10.1016/j.bbrc.2006.02.005. Epub 2006 Feb 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Clone Cells
  • Enzyme Inhibitors / pharmacology
  • Interferon-gamma / pharmacology
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Lipopolysaccharides / pharmacology*
  • Macrophage Activation / immunology
  • Macrophages / enzymology*
  • Macrophages / immunology
  • Mice
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / biosynthesis*
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / physiology*
  • Proto-Oncogene Proteins c-vav / antagonists & inhibitors
  • Proto-Oncogene Proteins c-vav / metabolism
  • Recombinant Proteins
  • Tetracycline / pharmacology
  • Transfection
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / biosynthesis*

Substances

  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-vav
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Vav1 protein, mouse
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn6 protein, mouse
  • Tetracycline