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

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-1beta (IL-1beta). Since the enhanced IL-1beta 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-1beta 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-kappaB 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.

journal_name

Mol Cell Biol

authors

Sekine H,Mimura J,Oshima M,Okawa H,Kanno J,Igarashi K,Gonzalez FJ,Ikuta T,Kawajiri K,Fujii-Kuriyama Y

doi

10.1128/MCB.00337-09

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

6391-400

issue

24

eissn

0270-7306

issn

1098-5549

pii

MCB.00337-09

journal_volume

29

pub_type

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