Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/-induced in Vitro Osteoclastogenesis

Kan Saito, Naoya Oohara, Hitoshi Hotokezaka, Satoshi Fukumoto, Kenji Yuasa, Mariko Naito, Taku Fujiwara, Koji Nakayama

Research output: Contribution to journalArticle

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Abstract

Bacterial infection sometimes impairs bone metabolism. In this study, we infected the osteoblastic cell line MC3T3-E1 with Mycobacterium bovis bacillus Calmette-Guérin (BCG) and identified genes that were up-regulated in the BCG-infected cells by the suppression subtractive hybridization method. A gene encoding 4-1BB (CD137), a member of the tumor necrosis factor-α receptor family, was found to be one of the up-regulated genes. Up-regulation of 4-1BB was also observed by infection with Escherichia coli, Salmonella typhimurium, and Staphylococcus aureus, and by treatment with lipopolysaccharides and heat-killed BCG. Bone marrow cells and the macrophage-like cell lines J774 and RAW264.7 were found to express 4-1BB ligand (4-1BBL). Recombinant 4-1BB (r4-1BB) that was immobilized on culture plates strongly inhibited macrophage colony stimulating factor (M-CSF)/receptor activator of nuclear factor-κB ligand (RANKL)-induced in vitro osteoclast formation from bone marrow cells. Anti-4-1BBL antibody also inhibited osteoclast formation to a lesser extent, indicating involvement of reverse signaling through 4-1BBL during inhibition of osteoclast formation. A casein kinase I (CKI) inhibitor markedly suppressed the inhibitory effect of r4-1BB on M-CSF/ RANKL-induced osteoclast formation, suggesting that CKI might be involved in 4-1BB/4-1BBL reverse signaling. r4-1BB showed no effects on M-CSF- or RANKL-induced phosphorylation of I-κB, ERK1/2, p38, or JNK, whereas RANKL-induced phosphorylation of Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K), was completely abolished by r4-1BB, suggesting that 4-1BB/4-1BBL reverse signaling may interfere with PI3K/Akt pathway. r4-1BB also abolished RANKL-mediated induction of nuclear factor of activated T cells-2. This study may elucidate a novel role of 4-1BB in cell metabolism, especially osteoclastogenesis.

Original languageEnglish
Pages (from-to)13555-13563
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number14
DOIs
Publication statusPublished - Apr 2 2004
Externally publishedYes

Fingerprint

4-1BB Ligand
Macrophage Colony-Stimulating Factor
Osteogenesis
Osteoclasts
Up-Regulation
Bacilli
Casein Kinase I
Molecules
Cells
Phosphatidylinositol 3-Kinase
Bacillus
Infection
Bone
Phosphorylation
Metabolism
Bone Marrow Cells
Genes
Macrophage Colony-Stimulating Factor Receptors
NFATC Transcription Factors
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/-induced in Vitro Osteoclastogenesis. / Saito, Kan; Oohara, Naoya; Hotokezaka, Hitoshi; Fukumoto, Satoshi; Yuasa, Kenji; Naito, Mariko; Fujiwara, Taku; Nakayama, Koji.

In: Journal of Biological Chemistry, Vol. 279, No. 14, 02.04.2004, p. 13555-13563.

Research output: Contribution to journalArticle

Saito, Kan ; Oohara, Naoya ; Hotokezaka, Hitoshi ; Fukumoto, Satoshi ; Yuasa, Kenji ; Naito, Mariko ; Fujiwara, Taku ; Nakayama, Koji. / Infection-induced Up-regulation of the Costimulatory Molecule 4-1BB in Osteoblastic Cells and Its Inhibitory Effect on M-CSF/-induced in Vitro Osteoclastogenesis. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 14. pp. 13555-13563.
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