MCB Accepts, published online ahead of print on 12 October 2009

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Mol. Cell. Biol. doi:10.1128/MCB.00337-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Hypersensitivity of AhR-deficient mice to LPS-induced septic shock

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

The Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan; Division of Molecular Toxicology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun,Saitama 362-0806, Japan; SORST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, 332-0012, Japan

^* To whom correspondence should be addressed. Email: ykfujii{at}tara.tsukuba.ac.jp.

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 KO mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly due to the dysfunction of their macrophages. In response to LPS, AhR KO bone marrow-derived macrophages (BMDM) secreted an enhanced amount of IL-1. Since the enhanced IL-1 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-1 secretion by AhR KO BMDM. Analysis of gene expression revealed that AhR directly regulates the expression of Pai-2 through a mechanism involving NF-B, but not AhR nuclear translocator (Arnt) in a LPS-dependent manner. Together with the result that administration of the AhR ligand, 3-methylcholanthrene (3MC) partially protected AhR WT mice from endotoxin-induced death, these results raise the possibility that an appropriate AhR ligand may be useful for treating patients with inflammatory disorders.