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The expression of interleukin-12 is increased by MAP kinase phosphatase-1 through a mechanism related to interferon

Riku Korhonen1, Noora Huotari, Tuija Hömmö

  • 1The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland. riku.korhonen@uta.fi

Molecular Immunology
|April 3, 2012
PubMed

Insights

Mitogen-activated protein kinase phosphatase-1 (MKP-1) positively regulates Interleukin-12 (IL-12) expression by enhancing Interferon Regulatory Factor 1 (IRF1). This finding suggests MKP-1 supports Th1 immune responses and anti-microbial defense.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a nuclear phosphatase that typically inhibits p38 MAPK activity.
  • MKP-1 deficiency is known to cause excessive innate immunity and inflammatory gene expression.
  • The role of MKP-1 in regulating specific cytokine expression, such as IL-12, was previously unclear.

Purpose of the Study:

  • To investigate the role of MKP-1 in the regulation of Interleukin-12 (IL-12) expression in macrophages.
  • To elucidate the molecular mechanisms by which MKP-1 influences IL-12 production and Th1 immune responses.

Main Methods:

  • Utilized primary mouse peritoneal macrophages (PMs) and bone marrow-derived macrophages from MKP-1 deficient and wild-type mice.
  • Employed lipopolysaccharide (LPS) stimulation to induce inflammatory responses.
  • Used pharmacologic inhibitors (BIRB 796, SB 202190) of p38 MAPK and siRNA for Interferon Regulatory Factor 1 (IRF1) silencing.

Main Results:

  • LPS-induced IL-12p40 expression was significantly lower in MKP-1 deficient macrophages compared to wild-type, while TNF expression was elevated.
  • Inhibition of p38 MAPK by pharmacologic agents enhanced LPS-induced IL-12p40 production.
  • IRF1 was identified as a key regulator of IL-12p40 expression, and its expression was modulated by MKP-1 and p38 MAPK activity.

Conclusions:

  • MKP-1 acts as a positive regulator of IL-12 expression, contrasting with its known inhibitory role on p38 MAPK.
  • MKP-1 enhances IL-12 expression by promoting IRF1 expression, thereby supporting Th1-type immune responses.
  • These findings highlight MKP-1's critical role in anti-microbial defense through the regulation of IRF1 and IL-12.

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