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The function of mitogen-activated protein kinase phosphatase-1 in peptidoglycan-stimulated macrophages

Edward G Shepherd1, Qun Zhao, Stephen E Welty

  • 1Center for Developmental Pharmacology and Toxicology, Children's Research Institute, Children's Hospital, the Department of Pediatrics, Ohio State University, Columbus, Ohio 43205, USA.

The Journal of Biological Chemistry
|October 16, 2004
PubMed

Insights

MAP kinase phosphatase-1 (MKP-1) regulates inflammatory cytokine production in macrophages responding to Gram-positive bacteria. MKP-1 induction by peptidoglycan controls tumor necrosis factor-alpha and interleukin-1 beta release.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Mitogen-activated protein (MAP) kinases are crucial for macrophage inflammatory responses to lipopolysaccharides.
  • The role of MAP kinases and their regulation in macrophage responses to Gram-positive bacteria, like peptidoglycan, is not well understood.
  • Understanding MAP kinase regulation is key to controlling inflammatory cytokine production.

Purpose of the Study:

  • To investigate MAP kinase regulation in macrophages stimulated with peptidoglycan.
  • To determine the role of MAP kinase phosphatase (MKP)-1 in controlling pro-inflammatory cytokine production.
  • To elucidate the function of MKP-1 in primary macrophages during Gram-positive bacterial infection.

Main Methods:

  • Murine RAW264.7 and primary peritoneal macrophages were stimulated with peptidoglycan.
  • MAP kinase activation and dephosphorylation were assessed.
  • MKP-1 expression was modulated using triptolide, overexpression, and small interfering RNA (siRNA).
  • Production of tumor necrosis factor (TNF)-alpha and interleukin-1 beta was quantified.

Main Results:

  • Peptidoglycan induced transient activation of JNK, p38, and ERK, accompanied by potent MKP-1 induction and MAP kinase dephosphorylation.
  • Triptolide inhibited MKP-1 induction, prolonging JNK and p38 activation.
  • MKP-1 overexpression attenuated TNF-alpha production, while MKP-1 knockdown increased TNF-alpha and interleukin-1 beta production.
  • MKP-1 induction correlated with JNK and p38 inactivation in primary macrophages, and its blockade sustained MAP kinase activation.

Conclusions:

  • MKP-1 plays a critical role in regulating TNF-alpha and interleukin-1 beta expression in macrophages stimulated by peptidoglycan.
  • MKP-1 is a key regulator of inflammatory responses in primary macrophages to Gram-positive bacterial components.
  • Targeting MKP-1 may offer a strategy to modulate macrophage inflammatory responses.

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