Open AccessIncretins amplify TNF-α-stimulated IL-6 synthesis in osteoblasts: Suppression of the IκB/NF-κB pathway
Author(s) -
Kazuo Fujita,
Harukuni Tokuda,
Naohiro Yamamoto,
Shingo Kainuma,
Tetsu Kawabata,
Go Sakai,
Gen Kuroyanagi,
Rie MatsushimaNishiwaki,
Atsushi Harada,
Osamu Kozawa,
Takanobu Otsuka
Publication year - 2017
Publication title -
international journal of molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.048
H-Index - 90
eISSN - 1791-244X
pISSN - 1107-3756
DOI - 10.3892/ijmm.2017.2892
Subject(s) - medicine , endocrinology , tumor necrosis factor alpha , protein kinase a , creb , adenylyl cyclase , phosphorylation , p70 s6 kinase 1 , kinase , osteoblast , biology , chemistry , microbiology and biotechnology , stimulation , protein kinase b , biochemistry , transcription factor , in vitro , gene
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.