The C/EBP beta isoform 34-kDa LAP is responsible for NF-IL-6-mediated gene induction in activated macrophages, but is not essential for intracellular bacteria killing.
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/EBPbeta in macrophages. To assess the function of the 34-kDa LAP in vivo, we generated knock-in mice, in which methionine 20 of C/EBPbeta, 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/EBPbeta 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/EBPbeta-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.
Uematsu
Satoshi
S
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan.
Kaisho
Tsuneyasu
T
Tanaka
Takashi
T
Matsumoto
Makoto
M
Yamakami
Megumi
M
Omori
Hiroko
H
Yamamoto
Masahiro
M
Yoshimori
Tamotsu
T
Akira
Shizuo
S
D000818:Animals; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology*; D007424:Intracellular Fluid / Q000276:immunology* / Q000382:microbiology*; D008089:Listeria monocytogenes / Q000254:growth & development / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D020033:Protein Isoforms / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation
D022782:CCAAT-Enhancer-Binding Protein-beta; D020033:Protein Isoforms