Olive polyphenols attenuate TNF-α-stimulated M-CSF and IL-6 synthesis in osteoblasts: Suppression of Akt and p44/p42 MAP kinase signaling pathways

• Published in: Biomedicine & pharmacotherapy Vol. 141; p. 111816
• Main Authors: Hioki, Tomoyuki, Tokuda, Haruhiko, Kuroyanagi, Gen, Kim, Woo, Tachi, Junko, Matsushima-Nishiwaki, Rie, Iida, Hiroki, Kozawa, Osamu
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2021; Elsevier
• Subjects: 3T3 Cells; Animals; Culture Media, Conditioned; Interleukin-6; Interleukin-6 - biosynthesis; Iridoid Glucosides - pharmacology; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - biosynthesis; MAP Kinase Signaling System - drug effects; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Olea - chemistry; Olive polyphenol; Oncogene Protein v-akt - antagonists & inhibitors; Osteoblast; Phenylethyl Alcohol - analogs & derivatives; Phenylethyl Alcohol - pharmacology; Polyphenols - pharmacology; Rotenone - analogs & derivatives; Rotenone - pharmacology; Signal Transduction - drug effects; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor necrosis factor-α; RANKL; α-MEM; M-CSF; Macrophage colony-stimulating factor; MAP kinase; RANK; PI3-kinase; Olive polyphenol; Tumor necrosis factor-α; IL-6; Interleukin-6; IκB; NF-κB; TNF-α; RT-PCR; FBS; Osteoblast; ELISA
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111816

Olive oil polyphenols, which possess cytoprotective activities like anti-oxidant and anti-inflammatory effects, could modulate osteoblast functions. The aim of this study is to elucidate the effects and the underlying mechanisms of hydroxytyrosol and oleuropein on the tumor necrosis factor-α (TNF-α)-induced macrophage colony-stimulating factor (M-CSF) and interleukin-6 (IL-6) synthesis in osteoblasts. Osteoblast-like MC3T3-E1 cells were pretreated with hydroxytyrosol, oleuropein, deguelin, PD98059 or wedelolactone, and then stimulated by TNF-α. The levels of M-CSF and IL-6 in the conditioned medium were determined with ELISA. The mRNA expression levels of M-CSF or IL-6 were determined with real-time RT-PCR. The phosphorylation levels of Akt, p44/p42 mitogen-activated protein (MAP) kinase or NF-κB in the cell lysates were determined with Western blot analysis. Hydroxytyrosol and oleuropein attenuated the TNF-α-stimulated M-CSF release. Deguelin, an inhibitor of Akt, significantly suppressed the TNF-α-stimulated M-CSF release, which failed to be affected by the MEK1/2 inhibitor PD98059 or the IκB inhibitor wedelolactone. Hydroxytyrosol and oleuropein suppressed the TNF-α-induced phosphorylation of Akt and p44/p42 MAP kinase. Hydroxytyrosol and oleuropein attenuated the TNF-α-stimulated IL-6 release. Hydroxytyrosol suppressed the TNF-α-induced mRNA expressions of M-CSF and IL-6. Hydroxytyrosol or oleuropein failed to affect the cell viability. Our present findings strongly suggest that olive oil polyphenols hydroxytyrosol and oleuropein down-regulates TNF-α signaling at the points upstream of Akt and p44/p42 MAP kinase in osteoblasts, leading to the attenuation of M-CSF and IL-6 synthesis. •Hydroxytyrosol and oleuropein suppressed TNF-α-stimulated M-CSF and IL-6 release.•Hydroxytyrosol suppressed TNF-α-induced mRNA expressions of M-CSF and IL-6.•Not PD98059 but deguelin suppressed TNF-α-stimulated M-CSF release.•Hydroxytyrosol and oleuropein suppressed TNF-α-induced Akt phosphorylation.•Hydroxytyrosol and oleuropein suppressed TNF-α-induced p44/p42 MAPK phosphorylation.