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

Amy O Hardin1, Elizabeth A Meals, Taolin Yi

  • 1Children's Foundation Research Center at Le Bonheur Children's Medical Center, Room 301 West Patient Tower, 50 North Dunlap, Memphis, TN 38103, USA.

Biochemical and Biophysical Research Communications
|February 21, 2006
PubMed

Insights

Protein tyrosine phosphatase SHP-1 negatively regulates macrophage activation. Overexpressing SHP-1 in macrophages inhibited TNF and iNOS production, suggesting SHP-1 dephosphorylates vav1 to control immune responses.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Protein tyrosine phosphatases (PTPs) like CD45 and SHP-1 are implicated in regulating macrophage activation.
  • Mice deficient in SHP-1 exhibit hyper-responsive macrophages, suggesting a negative regulatory role for SHP-1.

Purpose of the Study:

  • To provide direct evidence for SHP-1's inhibitory role in lipopolysaccharide (LPS)-induced macrophage activation.
  • To investigate the molecular mechanisms underlying SHP-1-mediated regulation of macrophage activation.

Main Methods:

  • Utilized a RAW 264.7 macrophage subclone (RAW-TT10 cells) for repressible/inducible overexpression of wild-type and truncated SHP-1.
  • Stimulated macrophages with lipopolysaccharide (LPS) and recombinant murine interferon-gamma.
  • Assessed Tumor Necrosis Factor (TNF) secretion and inducible Nitric Oxide Synthase (iNOS) protein levels.
  • Analyzed LPS-mediated tyrosine phosphorylation of the vav1 protein.

Main Results:

  • Overexpression of wild-type SHP-1 significantly inhibited LPS- and interferon-gamma-induced TNF secretion and iNOS accumulation.
  • SHP-1 overexpression diminished LPS-mediated tyrosine phosphorylation of vav1.
  • Expression of a dominant-negative truncated SHP-1 construct modestly increased TNF and iNOS production and did not affect vav1 phosphorylation.

Conclusions:

  • SHP-1 directly inhibits LPS-induced macrophage activation.
  • The inhibitory effect of SHP-1 may be mediated, in part, through the dephosphorylation of vav1.
  • These findings elucidate a key regulatory mechanism in macrophage immune responses.

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