Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock

Abstract

MOLECULAR AND CELLULAR BIOLOGY, Dec. 2009, p. 6391–6400 Vol. 29, No. 24 0270-7306/09/$12.00 doi:10.1128/MCB.00337-09 Copyright © 2009, American Society for Microbiology. All Rights Reserved. Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock
† Hiroki Sekine,1,5 Junsei Mimura,1,5 Motohiko Oshima,1,5 Hiromi Okawa,1,5 Jun Kanno,2 Katsuhide Igarashi,2 Frank J. Gonzalez,3 Togo Ikuta,4 Kaname Kawajiri,4 and Yoshiaki Fujii-Kuriyama1,5* The Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan1; Division of Molecular Toxicology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan2; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208923; Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan4; and SORST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, 332-0012, Japan5 Received 16 March 2009/Returned for modification 2 May 2009/Accepted 11 September 2009 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 demon- strate 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-1
(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

Key Biomarkers

Symptom Clusters