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The C/EBP Isoform 34-kDa LAP Is Responsible for NF-IL-6-Mediated Gene Induction in Activated Macrophages, but Is Not Essential for Intracellular Bacteria Killing¹

Satoshi Uematsu^*, Tsuneyasu Kaisho, Takashi Tanaka, Makoto Matsumoto, Megumi Yamakami^¶, Hiroko Omori^¶, Masahiro Yamamoto^*, Tamotsu Yoshimori^¶ and Shizuo Akira^2,*,

^* Department of Host Defense, Research Institute for Microbial Diseases, Osaka University and Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, Osaka, Japan; Laboratory for Host Defense, Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Kanagawa, Japan; Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan; and ^¶ Department of Cell Regulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

The C/ebpb gene is translated into three different protein isoforms, two transcriptional activating proteins (38-kDa Full and 34-kDa liver-enriched transcriptional activation protein (LAP)) and one transcriptional inhibitory protein, by alternative use of different AUG initiation codons within the same open reading frame. The isoform 34-kDa LAP is thought to be the most transcriptionally active form of C/EBP in macrophages. To assess the function of the 34-kDa LAP in vivo, we generated knock-in mice, in which methionine 20 of C/EBP, the start site for the 34-kDa LAP is replaced with an alanine. The expression of the 34-kDa LAP was abolished in C/ebpb^M20A/M20A mice. The induction of C/EBP target genes, such as inflammatory cytokines, chemokines, prostanoid synthetase, and antimicrobial peptides, was abolished in C/ebpb^M20A/M20A macrophages, and C/ebpb^M20A/M20A mice were susceptible to Listeria monocytogenes infection. Furthermore, the heat-killed Propionibacterium acnes-induced Th1 response, granuloma formation, and LPS shock were severely impaired. Nevertheless, impairment of intracellular bacteria killing, which is the most prominent phenotype in C/EBP-deficient mice, was not observed in C/ebpb^M20A/M20A mice. Collectively, we demonstrated that 34-kDa LAP is responsible for NF-IL6-mediated gene induction, but not essential for intracellular bacteria killing in activated macrophages.

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.

¹ This work was supported by grants from Special Coordination Funds, the Ministry of Education, Culture, Sports, Science and Technology, and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

² Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka, Japan. E-mail address: sakira{at}biken.osaka-u.ac.jp

³ Abbreviations used in this paper: LAP, liver-enriched transcriptional protein; LIP, liver-enriched transcriptional inhibitory protein; ES, embryonic stem.