p38 Mitogen-activated protein kinase mediates IL-8 induction by the ribotoxin deoxynivalenol in human monocytes

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Zahidul Islam1, Jennifer S Gray, James J Pestka

  • 1Department of Food Science and Human Nutrition, Michigan State University, 234 G.M. Trout Building, East Lansing, MI 48824-1224, USA.

Toxicology and Applied Pharmacology
|December 21, 2005
PubMed

Insights

Deoxynivalenol (DON) triggers the ribotoxic stress response, activating p38 mitogen-activated protein kinase (MAPK) in human monocytes. This activation is crucial for inducing inflammatory cytokine IL-8 and other proinflammatory gene expression.

Area of Science:

  • Immunology
  • Toxicology
  • Cell Biology

Background:

  • Deoxynivalenol (DON) is a ribotoxic trichothecene mycotoxin.
  • Mitogen-activated protein kinases (MAPKs) play critical roles in cellular signaling pathways.
  • Interleukin-8 (IL-8) is a key pro-inflammatory cytokine involved in immune responses.

Purpose of the Study:

  • To investigate the effects of DON on MAPK-mediated IL-8 expression in human monocytes.
  • To elucidate the role of p38 MAPK in DON-induced inflammatory responses.
  • To determine the mechanism by which DON activates p38 MAPK in monocytes.

Main Methods:

  • Primary human monocytes and peripheral blood mononuclear cells (PBMC) were treated with DON.
  • IL-8 mRNA, heteronuclear RNA (hnRNA), and protein expression were measured.
  • p38 MAPK phosphorylation and activity were assessed using Western blotting and specific inhibitors (SB203580).
  • Flow cytometry was used to analyze cell populations and marker expression.

Main Results:

  • DON induced IL-8 mRNA, hnRNA, and protein in a concentration-dependent manner in U937 monocytic cells.
  • IL-8 expression correlated with p38 MAPK phosphorylation and was inhibited by SB203580.
  • DON induced p38-dependent IL-8, IL-6, and IL-1beta expression in human PBMC.
  • DON-induced p38 activation occurred exclusively in CD14(+) monocytes and varied among individuals.
  • DON did not activate Toll-like receptors but other ribotoxins induced p38 phosphorylation.

Conclusions:

  • p38 MAPK activation is essential for DON-induced IL-8 and pro-inflammatory gene expression in human monocytes.
  • DON activates p38 MAPK in human monocytes through the ribotoxic stress response pathway.
  • These findings highlight the role of DON in modulating innate immune responses via the p38 MAPK signaling pathway.

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