title: AMPK limits IL-1-stimulated IL-6 synthesis in osteoblasts: involvement of IκB/NF-κB pathway.
abstract: AMP-activated protein kinase (AMPK) is currently known to act as a key regulator of metabolic homeostasis. Several biosynthetic enzymes for fatty acid or glycogen are recognized as the targets of AMPK. In the present study, we investigated the role of AMPK in the interleukin-1 (IL-1)-stimulated IL-6 synthesis in osteoblast-like MC3T3-E1 cells. IL-1 induced phosphorylation of AMPK-α (Thr-172), which regulates AMPK activities, and acetyl-CoA carboxylase, a direct substrate of AMPK. Compound C, an inhibitor of AMPK, which suppressed the IL-1-induced phosphorylation of acetyl-CoA carboxylase, increased the release and the mRNA level of IL-6 stimulated by IL-1. Transfection of AMPK siRNA-α also amplified the IL-1-stimulated IL-6 release compared to the control cells. On the other hand, IL-1 elicited the phosphorylation of IκB, which caused subsequent decrease of total level of IκB. Wedelolactone, an inhibitor of IκB kinase, which reduced the phosphorylation both of IκB and NF-κB, significantly enhanced the IL-1-stimulated IL-6 synthesis. Compound C remarkably suppressed the IL-1-induced phosphorylation of IκB. These results strongly suggest that AMPK negatively regulates IL-1-stimulated IL-6 synthesis through the IκB/NF-κB pathway in osteoblasts.
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kato
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Hideo
authors.initials: H
authors.lastname: Natsume
authors.forename: Akira
authors.initials: A
authors.lastname: Kondo
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ito
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D020672:I-kappa B Proteins / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D055372:AMP-Activated Protein Kinases