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mTOR signaling pathway regulates the IL-12/IL-10 axis in Leishmania donovani infection

Satyanarayana Swamy Cheekatla1, Amita Aggarwal, Sita Naik

  • 1Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

Medical Microbiology and Immunology
|May 14, 2011
PubMed

Insights

Leishmania parasites modulate interleukin-12 (IL-12) and IL-10 production via phosphatidylinositol 3-kinase (PI3K) and mTOR pathways. mTOR inhibitors like rapamycin show potential in reversing this modulation for disease control.

Area of Science:

  • Immunology
  • Molecular Biology
  • Parasitology

Background:

  • Interleukin-12 (IL-12) expression in macrophages is regulated by phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) pathways.
  • Leishmania parasites manipulate host immune responses, including cytokine production, during infection.

Purpose of the Study:

  • To investigate the downstream pathways of PI3K involved in the regulation of IL-12 and IL-10 by Leishmania donovani.
  • To explore the role of the mechanistic target of rapamycin (mTOR) pathway in Leishmania-induced cytokine modulation.

Main Methods:

  • Utilized THP-1-derived macrophages and human monocytes stimulated with L. donovani.
  • Employed inhibitors of mTOR (rapamycin) and PI3K (wortmannin) to assess their effects on cytokine production.
  • Measured phosphorylation of P70S6K as an indicator of mTOR activity.
  • Investigated the role of Toll-like receptor 2 (TLR2) in parasite-induced cytokine responses.

Main Results:

  • mTOR inhibition by rapamycin reversed L. donovani-induced modulation of IL-12 and IL-10 in macrophages.
  • L. donovani induced P70S6K phosphorylation, indicating mTOR activation, which was blocked by rapamycin and partially by wortmannin.
  • Evidence suggests a PI3K-independent pathway contributes to IL-12 and IL-10 modulation.
  • Blocking TLR2 attenuated IL-10 but not IL-12 production.

Conclusions:

  • The PI3K and mTOR pathways form an intracellular network controlling IL-12/IL-10 modulation by L. donovani.
  • mTOR inhibitors represent potential therapeutic agents to reverse Leishmania-induced immune suppression and manage the disease.

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