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J. Biol. Chem., Vol. 283, Issue 18, 12468-12477, May 2, 2008

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Class-specific Regulation of Pro-inflammatory Genes by MyD88 Pathways and IB^*

Hisako Kayama¹, Vladimir R. Ramirez-Carrozzi^¶1, Masahiro Yamamoto, Taketoshi Mizutani^||, Hirotaka Kuwata, Hideo Iba^||, Makoto Matsumoto, Kenya Honda, Stephen T. Smale^¶2, and Kiyoshi Takeda³

From the Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan, the ^¶Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, California 90095, the Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, and the ^||Department of Microbiology and Immunology, Division of Host-Parasite Interaction, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Toll-like receptors trigger the induction of primary response genes via MyD88-mediated activation of NF-B and other transcription factors. These factors then act in concert with primary response gene products to induce secondary response genes. Although the MyD88 pathway is important for the expression of both primary and secondary response genes, we show that the recruitment of NF-B, RNA polymerase, and the TATA-binding protein is MyD88-dependent only at secondary response genes. This selective dependence correlates with the fact that MyD88 is required for nucleosome remodeling and histone H3K4 trimethylation at secondary response promoters, whereas rapidly induced primary response promoters are assembled into poised MyD88-independent chromatin structures. At a subset of secondary response promoters, IB was identified as a selective regulator of H3K4 trimethylation and preinitiation complex assembly after nucleosome remodeling. These mechanistic distinctions advance our understanding of the diverse molecular cascades that underlie the differential regulation of pro-inflammatory genes.

Received for publication, December 6, 2007 , and in revised form, February 8, 2008.

^* This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, the Ministry of Health, Labor, and Welfare, the Tokyo Biochemical Research Foundation, the Cell Science Research Foundation, the Yakult Bio-Science Foundation, the Osaka Foundation for Promotion of Clinical Immunology, the Sumitomo Foundation, the Sankyo Foundation of Life Science, the Giannini Family Foundation (to V. R. R. C.), and the Howard Hughes Medical Institute (to S. T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed: HHMI/UCLA 6525 MRL, 675 Charles E. Young Dr. South, Los Angeles, CA 90095-1662. Fax: 310-206-8623; E-mail: smale{at}mednet.ucla.edu. ³ To whom correspondence may be addressed: 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Fax: 81-6-6879-3989; E-mail: ktakeda{at}ongene.med.osaka-u.ac.jp.

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