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p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection

Leesun Kim1, Laura Del Rio, Barbara A Butcher

  • 1Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|March 22, 2005
PubMed

Insights

Toxoplasma gondii infection activates p38 MAPK in macrophages, crucial for IL-12 production. This study reveals a novel MKK-independent p38 MAPK autophosphorylation mechanism during intracellular infection.

Area of Science:

  • Immunology
  • Cell Biology
  • Parasitology

Background:

  • Toxoplasma gondii is an intracellular protozoan pathogen.
  • Macrophages (Mphi) are key immune cells involved in host defense against T. gondii.
  • Mitogen-activated protein kinase (MAPK) pathways are critical signaling cascades in immune responses.

Purpose of the Study:

  • To elucidate the role of MAPK signaling in T. gondii-induced IL-12 production in mouse macrophages.
  • To investigate the specific MAPK pathways involved in T. gondii infection.
  • To explore novel mechanisms of p38 MAPK activation during intracellular protozoan infection.

Main Methods:

  • Utilized synthetic MAPK inhibitors and dominant-negative macrophage mutants.
  • Assessed Interleukin-12 (IL-12) production in response to T. gondii infection.
  • Examined the activation of upstream MAPK kinases (MKK3, MKK4, MKK6) and p38 MAPK.
  • Investigated the association of p38alpha MAPK with TGF-beta-activated protein kinase 1-binding protein-1 (TAB1).

Main Results:

  • T. gondii infection robustly activates p38 MAPK and JNK pathways in macrophages.
  • p38 MAPK and JNK are essential for parasite-induced IL-12 production.
  • Parasite infection activates MKK3, but MKK3 deficiency does not impair p38 MAPK activation or IL-12 production.
  • Demonstrated MKK-independent p38alpha MAPK activation via autophosphorylation, dependent on TAB1 association.
  • Observed TAB1-p38alpha MAPK complex formation correlating with p38 MAPK phosphorylation during infection.
  • A p38 catalytic-site inhibitor blocked tachyzoite-induced p38alpha MAPK phosphorylation.

Conclusions:

  • p38 MAPK and JNK signaling are critical for T. gondii-mediated IL-12 production in macrophages.
  • MKK3 is not the sole activator of p38 MAPK in this context.
  • This study provides the first evidence of p38 MAPK autophosphorylation triggered by intracellular protozoan infection, highlighting a novel regulatory mechanism.

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