Hypersensitivity of aryl hydrocarbon receptor-deficient mice to lipopolysaccharide-induced septic shock

Hiroki Sekine, Junsei Mimura, Motohiko Oshima, Hiromi Okawa, Jun Kanno, Katsuhide Igarashi, Frank J. Gonzalez, Togo Ikuta, Kaname Kawajiri, Yoshiaki Fujii-Kuriyama

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)

Abstract

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is known to mediate a wide variety of pharmacological and toxicological effects caused by polycyclic aromatic hydrocarbons. Recent studies have revealed that AhR is involved in the normal development and homeostasis of many organs. Here, we demonstrate that AhR knockout (AhR KO) mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly due to the dysfunction of their macrophages. In response to LPS, bone marrow-derived macrophages (BMDM) of AhR KO mice secreted an enhanced amount of interleukin-1β (IL-1β). Since the enhanced IL-1β secretion was suppressed by supplementing Plasminogen activator inhibitor-2 (Pai-2) expression through transduction with Pai-2-expressing adenoviruses, reduced Pai-2 expression could be a cause of the increased IL-1β secretion by AhR KO mouse BMDM. Analysis of gene expression revealed that AhR directly regulates the expression of Pai-2 through a mechanism involving NF-κB but not AhR nuclear translocator (Arnt), in an LPS-dependent manner. Together with the result that administration of the AhR ligand 3-methylcholanthrene partially protected mice with wild-type AhR from endotoxin-induced death, these results raise the possibility that an appropriate AhR ligand may be useful for treating patients with inflammatory disorders.

Original languageEnglish
Pages (from-to)6391-6400
Number of pages10
JournalMolecular and cellular biology
Volume29
Issue number24
DOIs
Publication statusPublished - 2009 Dec

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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