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Reverse signaling through transmembrane TNF confers resistance to lipopolysaccharide in human monocytes and

G Eissner1, S Kirchner, H Lindner

  • 1Department of Hematology and Oncology, University of Regensburg, Germany. guenther.eissner@klinik.uni-regensburg.de

Journal of Immunology (Baltimore, Md. : 1950)
|June 8, 2000
PubMed

Insights

Monocytes (MO) induce endothelial cell (EC) apoptosis via TNF-alpha. Reverse signaling via transmembrane TNF-alpha (mTNF) from EC to MO prevents soluble apoptotic factors and confers lipopolysaccharide (LPS) resistance to MO.

Area of Science:

  • Immunology
  • Cell Biology
  • Endothelial Cell Biology

Background:

  • CD14+ monocytes induce endothelial cell (EC) apoptosis upon lipopolysaccharide (LPS) stimulation.
  • Apoptosis occurs via transmembrane TNF-alpha (mTNF) and soluble factors.
  • Neutralizing anti-TNF antibodies blocked apoptosis, suggesting a reverse signal.

Purpose of the Study:

  • To investigate the hypothesis of a bidirectional cross-talk between monocytes (MO) and EC.
  • To determine if reverse signaling via mTNF prevents soluble apoptotic factor production.

Main Methods:

  • Coculture of human microvascular EC with MO, MPhi, or Mono Mac 6, followed by LPS stimulation.
  • Treatment of cocultures with TNF-reactive agents (mAb, soluble receptors).
  • Analysis of cell-free supernatants for EC apoptosis-inducing activity and cytokine levels.

Main Results:

  • Preincubation of EC with MO/MPhi blocked EC apoptosis induction by LPS-stimulated cells.
  • TNF-reactive agents blocked the production of soluble death factors.
  • Reverse signaling conferred LPS resistance to MO/MPhi, down-regulating LPS-induced TNF, IL-6, IL-1, and IL-10.

Conclusions:

  • Bidirectional cross-talk exists between MO and EC.
  • Reverse signaling via mTNF from EC to MO prevents soluble apoptotic factor production.
  • This reverse signaling confers LPS resistance to monocytes.

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