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Updated: Aug 30, 2026

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the

Silvia Kirchner1, Simone Boldt, Walter Kolch

  • 1Department of Hematology, University of Regensburg, Regensburg, Germany.

Journal of Leukocyte Biology
|November 13, 2003
PubMed

Insights

Transmembrane tumor necrosis factor (mTNF) binding to endothelial cells triggers reverse signaling in monocytes/macrophages, conferring resistance to lipopolysaccharide (LPS) by blocking inflammatory pathways.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • Transmembrane tumor necrosis factor (mTNF) on monocytes/macrophages induces apoptosis in endothelial cells via direct contact or a soluble factor.
  • mTNF also functions as a receptor, initiating reverse signaling into monocytes/macrophages upon binding to TNF receptors on endothelial cells.
  • This reverse signaling confers resistance to bacterial lipopolysaccharide (LPS) and inhibits the production of death factor X and proinflammatory cytokines.

Purpose of the Study:

  • To investigate the specific signaling pathways utilized by mTNF when acting as a receptor.
  • To elucidate the mechanisms by which mTNF-mediated reverse signaling confers LPS resistance in monocytic cells.

Main Methods:

  • Utilized protein kinase C (PKC) inhibitors to distinguish between distinct reverse signaling pathways.
  • Investigated the role of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway in response to mTNF reverse signaling and LPS stimulation.

Main Results:

  • Reverse signaling activates two independent pathways, one dependent on PKC (suppressing death factor X) and another independent of PKC (suppressing cytokine release).
  • Both LPS and mTNF reverse signaling activate the MAPK/ERK pathway.
  • Activation of mTNF reverse signaling renders monocytes/macrophages refractory to subsequent LPS-induced MAPK/ERK activation.

Conclusions:

  • mTNF reverse signaling confers LPS resistance by interfering with key signal-transduction pathways, specifically the MAPK/ERK pathway.
  • Distinct PKC-dependent and PKC-independent pathways mediate the effects of mTNF reverse signaling on monocytic cells.
  • Understanding these pathways offers insights into the immunomodulatory functions of mTNF in monocyte and macrophage responses.

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