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Lipoarabinomannan-induced cell signaling involves ceramide and mitogen-activated protein kinase

Madhumita Sirkar1, Subrata Majumdar

  • 1Department of Microbiology, Bose Institute, Calcutta 700 054, India.

Clinical and Diagnostic Laboratory Immunology
|November 5, 2002
PubMed

Insights

Lipoarabinomannan (LAM) from Mycobacterium tuberculosis promotes host cell survival by generating ceramide, a second messenger. This process involves altered signaling pathways and enhanced protein kinase activity, ultimately aiding cell survival.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Lipoarabinomannan (LAM) is a major cell wall component of mycobacteria.
  • Previous studies showed LAM from Mycobacterium smegmatis inhibits protein kinase C, causing cytotoxicity.
  • Mycobacterium tuberculosis LAM's role in host cell survival was previously unknown.

Purpose of the Study:

  • To investigate the mechanism by which LAM from Mycobacterium tuberculosis influences host cell survival.
  • To identify the signaling pathways and molecules involved in LAM-induced cell survival.

Main Methods:

  • Treatment of human peripheral blood mononuclear cells with LAM.
  • Measurement of endogenous ceramide levels.
  • Analysis of protein tyrosine phosphorylation, including p42 mitogen-activated protein kinase and phosphoinositol 3-kinase (PI3 kinase).
  • Use of wortmannin, a PI3 kinase inhibitor.
  • Exogenous application of C(2)-ceramide.
  • Fluorescence-activated cell sorter analysis and morphological studies.

Main Results:

  • LAM treatment significantly increased endogenous ceramide levels in mononuclear cells.
  • LAM enhanced tyrosine phosphorylation of p42 mitogen-activated protein kinase and PI3 kinase.
  • LAM induced dephosphorylation of stress-activated protein kinase.
  • LAM-induced phosphorylation of p42 (extracellular signal-regulated kinase 2) was potentiated by wortmannin.
  • LAM treatment led to increased cell survival, confirmed by FACS and morphological analysis.

Conclusions:

  • LAM from Mycobacterium tuberculosis induces a signal transduction pathway that promotes host cell survival.
  • Ceramide generation is a key mechanism in LAM-mediated cell survival.
  • LAM alters protein kinase signaling, including p42 MAPK and PI3K pathways, contributing to cell viability.

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