title: Incretins amplify TNF-α-stimulated IL-6 synthesis in osteoblasts: Suppression of the IκB/NF-κB pathway.
abstract: Incretins including glucagon-like peptide-1 (GLP-1) and glucose‑dependent insulinotropic polypeptide (GIP) secreted from the small intestine after oral food ingestion are currently recognized to stimulate insulin secretion from pancreatic β cells. We previously reported that p70 S6 kinase limits the tumor necrosis factor‑α (TNF‑α)‑stimulated interleukin-6 (IL‑6) synthesis in osteoblast‑like MC3T3‑E1 cells. In the present study, we investigated the effects of incretins on the TNF‑α‑induced IL‑6 synthesis and the underlying mechanism in MC3T3‑E1 cells. GLP‑1 and GIP significantly upregulated both TNF‑α‑stimulated IL‑6 release and mRNA levels. Wedelolactone, an inhibitor of IκB kinase, amplified the TNF-α-induced IL‑6 release. GLP‑1 significantly attenuated the TNF‑α‑induced phosphorylation of IκB without affecting the phosphorylation of p70 S6 kinase. On the other hand, GLP‑1 markedly induced the phosphorylation of cAMP response element-binding protein (CREB). H‑89, an inhibitor of protein kinase A, significantly suppressed the enhancement by GLP-1 of TNF-α-stimulated IL‑6 release. Dibutyryl cAMP, a permeable analogue of cAMP, which suppressed the TNF-α-induced IκB phosphorylation, amplified the IL‑6 release. These results strongly suggest that incretins upregulate the TNF-α-stimulated IL‑6 synthesis in osteoblasts, and that the amplifying effect of incretin is exerted via reducing the IκB/NF‑κB pathway through the adenylyl cyclase-cAMP system.
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Tokuda
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kainuma
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kawabata
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Sakai
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Kuroyanagi
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.affiliation: Department of Orthopedic Surgery, National Center for Geriatrics and Gerontology, Obu, Aichi 474‑8511, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Harada
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.affiliation: Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism*; D054795:Incretins / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D020672:I-kappa B Proteins; D054795:Incretins; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP